Tricyclic compound having anti-allergic activities

ABSTRACT

A nitrogen-containing tricyclic compound represented by formula (I): ##STR1## a salt thereof, or a solvate of said compound or said salt, wherein R represents phenyl or naphthyl group which is unsubstituted or substituted at one to five sites with a group such as a halogen atom; a straight chain or branched alkyl group containing 1 to 10 carbon atoms which is unsubstituted or substituted with one or more halogen atoms; or the like; Y represents hydrogen atom; and Z represents a group such as hydrogen atom, hydroxyl group, or the like; or Y and Z together represent a group such as hydrazono group, hydroxyimino group, or the like which is unsubstituted or substituted with a particular group; and X 1  -X 2  ˜C˜X 3  represents CH--N--C═C or N--C═C--N; provided that when X 1  -X 2  ˜C˜X 3  represents N--C═C--N, Y and Z does not together represent hydroxyimino group or oxygen atom; is capable of inhibiting the production of IgE antibody, and therefore, is useful as a prophylactic and/or therapeutic agent for allergic diseases.

CROSS-REFERENCE

This application is a 371 or PCT/JP 93/00549 filed Apr. 27, 1993.

FIELD OF THE INVENTION

This invention relates to a prophylactic and/or therapeutic agent forallergic diseases wherein immunoglobulin E antibody (hereinafterreferred to as IgE antibody) is involved, for example, some types ofbronchial asthma, conjunctivitis, rhinitis, dermatis, andhypersensitivity.

BACKGROUND ART

Allergic reactions involved in allergic diseases, for example, sometypes of bronchial asthma, conjunctivitis, rhinitis, dermatis, andhypersensitivity are caused by the release of various chemical mediatorssuch as histamine, prostaglandin, leukotriene, thromboxane, and plateletactivating factor from mast cells or basophils upon binding of theparticular antigen with IgE antibody on the surface of such cells.Various symptoms are induced by such allergic reactions, and nosotropictherapies are most commonly employed to relieve such symptoms.Etiotropic therapies are also popular that employ compounds such assodium cromoglicate, tranilast, ketotifen, and azelastine, that arecapable of inhibiting the release of chemical mediators among the seriesof allergic reactions. However, compounds that are capable of blockingthe stage of reactions preceding the release of chemical mediators arescarcely known, and the development of such compounds useful forpharmaceutical composition is sincerely awaited. In view of suchconditions, a compound capable of inhibiting the production of IgEantibody, that is responsible for various allergic diseases as mentionedabove, would be highly useful as a therapeutic agent to enable the moreetiotropic treatment of such diseases.

Prior arts relating to the compound of the present invention arehereinafter described.

U.S. Pat. No. 3,200,123 discloses2-substituted-5,6-dihydroimidazo[ij]quinoline derivatives having aninflammatory activity without any pharmacological data. intensity anddetailed mechanism of such activity of the individual compound areunknown. In Journal of Organic Chemistry, 25, 1138-1147, 1960, theinventors of the U.S. Pat. No. 3,200,123 reported that only somecompounds among the above-mentioned dihydroimidazo[ij]quinolinederivatives proved effective in animals with dextran sulfate-inducededema. Both prior art documents fail to indicate anti-allergicactivities, in particular, the activity to suppress IgE antibodyproduction.

Some 1-substituted-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinoline derivativesare reported in Bulletin of the Chemical Society of Japan, 61, 423-429,1988. These compounds are intermediate products in the synthesis of3-phenyl-4H-benzo[hi]pyrrolo[2,1,5-cd]indolizine-4-one compounds, whoseelectronic features are of engineering interest. This document does notat all disclose pharmacological activities.

Chemical and Pharmaceutical Bulletin, 34, 2435-2442, 1986 disclosestricyclic and tetracyclic indolizine compounds having anti-allergicactivities. However, these compounds significantly differ from thecompounds of the present invention in their types of substituents andsites of the substitution. Further this document also fails to disclosespecific biological activities.

Journal of Medicinal Chemistry, 28, 298-302, 1985 discloses that PCAreaction is suppressed in rat by a6-oxo-6H-imidazo[4,5,1-ij]quinoline-4-carboxylic acid derivative.However, it is also disclosed in this document that this compoundsimultaneously proved to be toxic to kidney. The compound of thisdocument differs from the compounds of the present invention in itsstructure. This document also fails to refer to the activity ofinhibiting the IgE antibody production.

There are known many other compounds that have the nitrogen-containingtricyclic skeleton identical with that of the compound of the presentinvention. However, no report has so far indicated the anti-allergicactivity.

Among a variety of therapeutic agents for allergic diseases that havebeen developed, compounds disclosed in Japanese Patent ApplicationLaid-Open (Kokai) Nos. 59(1984)-167564, 1(1989)-149784, 2(1990)-25906,and the like are known to have been developed from the view point ofinhibiting the IgE antibody production. In the specification of some ofthese compounds, there are disclosures that some compounds inhibited theproduction of IgE antibody in some model animals. However, the degreesof the inhibitions are not quite sufficient, and none of such compoundshave so far been used as a commercial pharmaceutical agent, yet.

SUMMARY OF THE INVENTION

It has been recognized in animal experiments and in clinical practicethat the production of IgE antibody is induced by sensitization withparticular types of antigens, and the thus induced IgE production islikely to constitute for a considerably long period. Accordingly, atherapeutic agent for allergic diseases that attempts to inhibit the IgEantibody production would be required to inhibit not only the IgEantibody production during immune response induction phase but also thesubsequent IgE antibody production that continues after the immuneresponse induction phase.

Under such conditions, there has been a demand for a therapeutic agentfor allergic diseases which is capable of sufficiently inhibiting theIgE antibody production for a considerably long period, and which ishighly active and safe upon administration to human.

In view of such above situation, the inventors of the present inventionhave for many years searched for a compound that is capable ofsufficiently inhibiting the continuous production of the IgE antibodywhich is responsible for the allergic diseases. After suchinvestigation, the inventors of the present invention found that thenitrogen-containing tricyclic compound and the salt thereof of thepresent invention are capable of sufficiently inhibiting the IgEantibody production for a prolonged period. The present invention hasbeen completed on such a finding.

According to the present invention, there is provided anitrogen-containing tricyclic compound represented by formula (I):##STR2## a salt thereof, or a solvate of said compound or said salt,wherein

R represents phenyl or naphthyl group which is unsubstituted orsubstituted at one to five sites with a group optionally selected from ahalogen atom; a straight chain or branched alkyl group containing 1 to10 carbon atoms which is unsubstituted or substituted with one or morehalogen atoms; cyano group; carboxyl group; an alkoxycarbonyl groupcontaining 1 to 4 carbon atoms; hydroxyl group; a straight chain orbranched alkoxyl group containing 1 to 4 carbon atoms which isunsubstituted or substituted with one or more halogen atoms; phenoxygroup; tetrazolyl group; amino group which is unsubstituted orsubstituted at least at one site with a straight chain or branched alkylgroup containing 1 to 4 carbon atoms; and nitro group;

Y represents hydrogen atom; and

Z represents hydrogen atom; hydroxyl group; acetoxy group; amino groupwhich is unsubstituted or substituted with methylthiopropanoyl group, analkyl group containing 1 to 4 carbon atoms, an aminoalkyl groupcontaining 1 to 4 carbon atoms, hydroxyethylaminoethyl group, analkoxyoxalyl group containing 1 to 4 carbon atoms, or an alkylidenegroup containing 2 to 6 carbon atoms; nitro group; or an alkyl groupcontaining 1 to 4 carbon atoms substituted with amino group; or

Y and Z together represent hydrazono group which is unsubstituted orsubstituted at least at one site with an alkyl group containing 1 to 4carbon atoms, an alkylidene group containing 2 to 6 carbon atoms, analkoxycarbonyl group containing 1 to 4 carbon atoms, phenyl group, tosylgroup, formyl group, carbamoyl group, amidino group, imidazolidinylgroup, pyridyl group, or methoxyphenylethylpiperidinylcarbonyl group;hydroxyimino group which is unsubstituted or substituted with an alkylgroup containing 1 to 4 carbon atoms which is unsubstituted orsubstituted with an alkoxycarbonyl group containing 1 to 4 carbon atomsor carboxyl group, tosyl group, or tetrazolylmethyl group; imino groupsubstituted with an unsubstituted or substituted heteromonocyclic group;methylene group which is unsubstituted or substituted with cyano groupor an aminoalkyl group containing 1 to 4 carbon atoms; or oxygen atom;and

X¹ -X² ˜C˜X³ represents CH--N--C═C or N--C═C--N; provided that when X¹-X² ˜C˜X³ represents N--C═C--N, Y and Z do not together representhydroxyimino group or oxygen atom. According to the present invention,there are also provided a process for producing such a compound, as wellas a therapeutic agent for allergic diseases characterized by theinclusion of such a compound.

When Y and Z together represent hydrazono group which is unsubstitutedor substituted at least at one site with an alkyl group containing 1 to4 carbon atoms, an alkylidene group containing 2 to 6 carbon atoms, analkoxycarbonyl group containing 1 to 4 carbon atoms, phenyl group, tosylgroup, formyl group, carbamoyl group, amidino group, imidazolidinylgroup, pyridyl group, or alkoxyphenylalkylpiperidinylcarbonyl group;hydroxyimino group which is unsubstituted or substituted with an alkylgroup containing 1 to 4 carbon atoms which is unsubstituted orsubstituted with an alkoxycarbonyl group or carboxyl group, tosyl group,or tetrazolylmethyl group; imino group substituted with an unsubstitutedor substituted heteromonocyclic group; or methylene group which issubstituted with cyano group or an aminoalkyl group in the compound ofthe formula (I), a syn-isomer, an anti-isomer, and mixtures thereof maybe present for each of the N--N bond in the hydrazono group, the N--Obond in the hydroxyimino group, the bond between the heteromonocyclicgroup and nitrogen atom of the imino group, and the bond between thecyano or the aminoalkyl group and the methylene group. It should beunderstood that all of such isomers and the mixtures thereof are withinthe scope of the present invention.

Furthermore, when Y represents hydrogen atom and Z represents a groupother than hydrogen atom in the compound of the formula (I), two opticalisomers are present. It should be understood that both optical isomersand the mixtures thereof are also within the scope of the presentinvention.

The nitrogen-containing tricyclic compound of the present invention iscapable of highly inhibiting the production of IgE antibody for aprolonged period, and simultaneously, has an activity to directlysuppress the release of histamine, which is known to be one of majorcauses for constriction of bronchial smooth muscle. Therefore, thetherapeutic agent for allergic diseases of the present invention may beused for preventing, relieving, and curing the allergic disease that aremediated by IgE antibody.

In the compounds of the present invention, R in formula (I) maypreferably be phenyl or naphthyl group which is unsubstituted orsubstituted at one to five sites with a group selected from a halogenatom; a straight chain or branched alkyl group containing 1 to 10 carbonatoms which is unsubstituted or substituted with one or more halogenatoms; a straight chain or branched alkoxyl group containing 1 to 4carbon atoms which is unsubstituted or substituted with one or morehalogen atoms; phenoxy group; and nitro group; and most preferably,phenyl group substituted at one or two sites with a group selected froma halogen atom; a straight chain or branched alkyl group containing 1 to6 carbon atoms which is substituted with one or more halogen atoms; anda straight chain or branched alkoxyl group containing 1 to 4 carbonatoms which is substituted with one or more halogen atoms.

The substituents Y and Z may preferably be such that Y representshydrogen atom, and Z represents hydrogen atom, hydroxyl group, acetoxygroup, amino group; or that Y and Z together represent hydrazono groupwhich is unsubstituted or independently substituted with one or moremembers selected from an alkyl group containing 1 to 4 carbon atoms, anaikylidene group containing 2 to 6 carbon atoms, and amidino group;hydroxyimino group which is unsubstituted or substituted with an alkylgroup containing 1 to 4 carbon atoms which is unsubstituted orsubstituted with an alkoxycarbonyl group, or tosyl group; methylenegroup which is unsubstituted or substituted with cyano group or anaminoalkyl group; or oxygen atom.

The compound represented by formula (lib'): ##STR3## wherein Rrepresents phenyl or naphthyl group which is unsubstituted orsubstituted at one to five sites with a group optionally selected from ahalogen atom; a straight chain or branched alkyl group containing 1 to10 carbon atoms which is unsubstituted or substituted with one or morehalogen atoms; cyano group; carboxyl group; an alkoxycarbonyl groupcontaining 1 to 4 carbon atoms; hydroxyl group; an alkoxyl groupcontaining 1 to 4 carbon atoms which is unsubstituted or substitutedwith one or more halogen atoms; phenoxy group; tetrazolyl group; aminogroup which is unsubstituted or substituted at least at one site with astraight chain or branched alkyl group containing 1 to 4 carbon atoms;and nitro group; and

X¹ -X² ˜C˜X³ represents N--C═C--N, which is an intermediate insynthesizing the nitrogen-containing tricyclic compound (I) of thepresent invention, also has a strong activity similar to that of thecompound of formula (I) to inhibit the production of IgE antibody, andaccordingly, it may be used for preventing or curing the allergicdiseases as described above.

The nitrogen-containing tricyclic compound of the present invention maybe produced by the production processes as described below, which may bemodified. With regard to the formulae that will be described below, thesubstituents in formula (I) are as defined above; and unless otherwisenoted, the substituents in other formulae are such that,

R represents phenyl or naphthyl group which is unsubstituted orsubstituted at one to five sites with a group optionally selected from ahalogen atom; a straight chain or branched alkyl group containing 1 to10 carbon atoms which is unsubstituted or substituted with one or morehalogen atoms; cyano group; carboxyl group; an alkoxycarbonyl groupcontaining 1 to 4 carbon atoms; hydroxyl group; a straight chain orbranched alkoxyl group containing 1 to 4 carbon atoms which isunsubstituted or substituted with one or more halogen atoms; phenoxygroup; tetrazolyl group; amino group which is unsubstituted orsubstituted at least at one site with a straight chain or branched alkylgroup containing 1 to 4 carbon atoms; and nitro group;

Y represents hydrogen atom; and

Z represents hydrogen atom; hydroxyl group; acetoxy group; amino groupwhich is unsubstituted or substituted with methylthiopropanoyl group, analkyl group containing 1 to 4 carbon atoms, an aminoalkyl groupcontaining 1 to 4 carbon atoms, hydroxyethylaminoethyl group, analkoxyoxalyl group containing 1 to 4 carbon atoms, or an alkylidenegroup containing 2 to 6 carbon atoms; nitro group; or an alkyl groupcontaining 1 to 4 carbon atoms substituted with amino group; or

Y and Z together represent hydrazono group which is unsubstituted orsubstituted at least at one site with an alkyl group containing 1 to 4carbon atoms, an alkylidene group containing 2 to 6 carbon atoms, analkoxycarbonyl group containing 1 to 4 carbon atoms, phenyl group, tosylgroup, formyl group, carbamoyl group, amidino group, imidazolidinylgroup, pyridyl group, or methoxyphenylethylpiperidinylcarbonyl group;hydroxyimino group which is unsubstituted or substituted with an alkylgroup containing 1 to 4 carbon atoms which is unsubstituted orsubstituted with an alkoxycarbonyl group containing 1 to 4 carbon atomsor carboxyl group, tosyl group, or tetrazolylmethyl group; imino groupsubstituted with an unsubstituted or substituted heteromonocyclic group;methylene group which is unsubstituted or substituted with cyano groupor an aminoalkyl group containing 1 to 4 carbon atoms; or oxygen atom;

X¹ -X² ˜C˜X³ represents CH--N--C═C or N--C═C--N; and

X represents a leaving group such as a halogen atom. ##STR4##

Next, processes for producing the compound of the present invention areschematically shown, and each reaction process is described. ##STR5##

A ketone derivative of formula (II), which is a known compound or may beproduced by the processes as will be described later, is reacted with ahydrazine or its salt in an aromatic hydrocarbon solvent; an inerthalogenated organic solvent such as dichloromethane or1,2-dichloroethane; an ethereal solvent such as diethylether ortetrahydrofurane, or dioxane; an alcoholic solvent such as ethanol ormethanol; or a mixture of such solvents at a temperature of from -70° C.to the boiling point of the solvent, and preferably, at room temperatureto 130° C. to produce a hydrazone represented by formula (IIa): ##STR6##wherein N˜N bond represents a syn- or an anti-bond; and R and X¹ -X²˜C˜X³ are as defined above for the nitrogen-containing tricycliccompound. Next, the thus produced hydrazone is optionally reacted with acompound represented by formula (III):

    R.sup.1 -X                                                 (III)

wherein X represents a leaving group, and R¹ represents phenyl group ortosyl group; or with a ketone or aldehyde containing 2 to 6 carbon atomsin the inert solvent as described above at a temperature of from -70° C.to the boiling point of the solvent, and preferably, at room temperatureto 130° C. to produce the compound of formula (I). (Production ProcessA)

Alternatively, the ketone derivative of formula (II) is reacted with acompound represented by formula (IV):

    H.sub.2 N-R.sup.2                                          (IV)

wherein R² represents amino group unsubstituted or substituted at leastone site with an alkyl group containing 1 to 4 carbon atoms, analkylidene group containing 2 to 6 carbon atoms, phenyl group, tosylgroup, formyl group, carbamoyl group, amidino group, imidazolidinylgroup, pyridyl group, or methoxyphenylethylpiperidinylcarbonyl group;hydroxyl group which is unsubstituted or substituted with an alkyl groupcontaining 1 to 4 carbon atoms which is unsubstituted or substitutedwith an alkoxycarbonyl group or carboxyl group, tosyl group, ortetrazolylmethyl group; an unsubstituted or substituted heteromonocyclicgroup in the inert solvent as described above selected from an aromatichydrocarbon solvent; an inert halogenated organic solvent such asdichloromethane or 1,2-dichloroethane; an ethereal solvent such asdiethylether or tetrahydrofurane, or dioxane; an alcoholic solvent suchas ethanol or methanol; and a mixture of such solvents at a temperatureof from -70° C. to the boiling point of the solvent, and preferably, atroom temperature to 130° C. to produce the compound of formula (I).(Production Process B)

Also, the ketone derivative of formula (II) may be reacted with ahydroxylamine or a its salt in an inert aromatic hydrocarbon solvent; aninert halogenated organic solvent such as dichloromethane or1,2-dichloroethane; an ethereal solvent such as diethylether ortetrahydrofurane, or dioxane; an alcoholic solvent such as ethanol ormethanol; and a mixture of such solvents at a temperature of from -70°C. to the boiling point of the solvent, and preferably, at roomtemperature to 130° C. to produce the corresponding oxime derivative(IIb): ##STR7## wherein N˜O bond represents a syn- or an anti-bond; andR and X¹ -X² ˜C˜X³ are as defined above.

The resulting oxime derivative may be either hydrogenated in thepresence of a metal catalyst such as palladium or reduced by suchcompound as lithium aluminum hydride to produce an amino derivative(which is a compound of formula (i) wherein Y is hydrogen atom and Z isamino group). If desired, the thus produced amino derivative may bereacted with a methylthiopropanoyl halide, an alkylhalide containing 1to 4 carbon atoms, or an alkoxyoxalyl halide containing 1 to 4 carbonatoms in the inert solvent as described above such as an aromatichydrocarbon solvent, a halogenated hydrocarbon solvent, or an etherealsolvent in the presence of a basic catalyst which may typically be atertiary amine such as triethylamine, pyridine, Dabco, or DBU at atemperature of from -70° C. to the boiling point of the solvent, andpreferably, at room temperature to 130° C. to produce the compound offormula (I).

The compound of formula (IIb) may be reacted with a halogenated alkylcontaining 1 to 4 carbon atoms which may be substituted or unsubstitutedwith carboxyl group or with tosyl halide, to modify the oxime group.

Furthermore, the compound of formula (II) may be reacted with ammoniumacetate in the above-described inert solvent, in an alcoholic solvent,or in the mixture of such inert solvent and the alcoholic solvent; andthe resulting compound may be treated with a reducing reagent such assodium cyanoborohydride. The resulting compound may be subjected to anoptional alkaline hydrolysis to produce an amino derivative.

Still further, the compound of formula (II) may be reacted with an aminederivative of formula (IV'):

    H.sub.2 N-R.sup.2'                                         (IV')

wherein R^(2') represents an alkyl group containing 1 to 4 carbon atoms,an aminoalkyl group containing 1 to 4 carbon atoms, orhydroxyethylaminoethyl group in the inert solvent as described above;and then, the resulting compound may be reduced with a reducing reagentsuch as sodium borohydride or hydrogenated in the presence of a metalcatalyst such as palladium or platinum oxide to produce a compoundrepresented by formula (I) which is a substituted amino derivative.

Still further, the compound of formula (II) may be subjected to anadequate reduction such as reduction with sodium borohydride orMeerwein-Ponndorf reduction to produce a hydroxy derivative. The thusobtained hydroxy derivative may be converted into either a halogenoderivative by using a halogenating reagent such as hydrogen chloride,phosphorus trichloride, phosphorus pentachloride, or phosphorusoxychloride, or a bromate corresponding to such chlorides; or into asulfonyloxy derivative by using an adequate sulfonylating agent such asmesylchloride or tosylchloride in a halogenated organic solvent such asdichloromethane or in an ethereal solvent such as diethylether,tetrahydrofurane, or dioxane at a temperature of from -70° C. to theboiling point of the solvent, and preferably, at room temperature to130° C. The resulting hydroxy or sulfonyloxy derivative may be reactedwith ammonia or an alkoxyoxalylamine containing 1 to 4 carbon atoms inthe inert solvent as described above such as an aromatic hydrocarbonsolvent, a halogenated hydrocarbon solvent, or an ethereal solvent inthe presence of a basic catalyst which may typically be a tertiary aminesuch as triethylamine, pyridine, Dabco, or DBU at a temperature of from-70° C. to the boiling point of the solvent, and preferably, at roomtemperature to 130° C. to produce the compound of formula (I).

Still further, the compound of formula (II) may be reacted with analkylphosphonium salt containing 1 to 5 carbon atoms which isunsubstituted or substituted with cyano group or amino group; or analkylphosphate ester corresponding to such an alkylphosphonium salt inan ethereal solvent such as diethylether, tetrahydrofurane, or dioxanein the presence of a base such as potassium hydroxide, potassiumt-butoxide or butyllithium at a temperature of from -70° C. to theboiling point of the solvent to produce the compound of formula (I).

Still further, a compound of formula (I) wherein both Y and Z arehydrogen atoms may be produced by further treating the hydrazonederivative produced in accordance with the Production Process A or Bwith sodium borohydride or heating the hydrazone derivative underalkaline conditions; by subjecting the compound of formula (II) toClemmensen reduction or thioketal reduction; or by subjecting theabove-described halogeno derivative or sulfonyloxy derivative, which isproduced by reduction of the ketone group of the compound of formula(II) to hydroxyl group, followed by halogenation or sulfonation, tohydrogenation in the presence of a metal catalyst such as palladium orreduction with such compound as lithium aluminum hydride. (ProductionProcess C)

The compound of formula (I) may be represented by the formula (VIII)when X¹ -X² ˜C˜X³ is CH--N--C═C. The compound of formula (VIII) may beproduced by the processes for the production of the compound of formula(I) as described above, and also, by the processes as described below.##STR8##

A compound of formula (V), which is already known compound or may beproduced by the process as will be described later, is reacted with anaromatic ketone derivative represented by formula (VI) in an inertbenzene solvent such as benzene, toluene or xylene to produce a5,6,7,8-tetrahydroquinolinium salt represented by formula (VII). Inprior art technique as disclosed in such document as Advances inHeterocyclic Chemistry, vol. 23, pages 103 to 170, 1978, Academic Press,the 5,6,7,8-tetrahydroquinolinium salt of formula (VII) is reacted withan inorganic base such as sodium hydrogencarbonate or potassiumcarbonate in a solvent such as water to produce the compound of formula(VIII). In the present invention, we have found that the compound offormula (VIII) may be produced at a high yield by reacting the5,6,7,8-tetrahydroquinolinium salt of formula (VII) with an organic basesuch as triethylamine in a solvent such as dimethylformamide ordimethylsulfoxide in the presence of a molecular sieves. In both steps,the reaction will proceed at a temperature in the range of from roomtemperature to the boiling point of the solvent. However, it ispreferable to heat the reaction system to about 100° C. (ProductionProcess D)

Alternatively, the compound of formula (V) may be reacted with an aceticacid derivative of formula (IX) in the inert benzene solvent asdescribed above to produce a 5,6,7,8-tetrahydroquinolinium salt (X). The5,6,7,8-tetrahydroquinolinium salt (X) may be reacted with a substitutedbenzoic acid anhydride of formula (XI) in the inert benzenoid solvent inthe presence of an organic base such as sodium benzoate to close thering. The ester residue on second site of the resultingpyrrolo[3,2,1-ij]quinoline is hydrolyzed and decarbonated to produce acompound of formula (VIII). In both steps, the reaction will proceed ata temperature in the range of from room temperature to the boiling pointof the solvent. However, it is preferable to heat the reaction system toabout 100° C. (Production Process E)

The group X to be eliminated in formula (VI) or (IX) used in ProductionProcess D or E may typically be a halogen atom such as chlorine atom orbromine atom; a sulfate ester such as p-toluenesulfonyloxy group ormethanesulfonyloxy group; or phosphate ester, among which the halogenatom being the most preferred in view of operation convenience,reactivity, and the like.

The compound of formula (I) may be represented by the formula (XIII)when X¹ -X² ˜C˜X³ is N--C═C--N. The compound of formula (XIII) may beproduced by the processes for the production of the compound of formula(I) as described above, and also, by the processes as described below.##STR9##

The compound of formula (XII), which is known compound or may beproduced by the process as will be described later, is used for thestarting material. This compound is reacted with an aldehyde of formula(XIV), an ortho acid ester of formula (XV), or an aromatic carboxylicacid of formula (XVI) to produce the compound of formula (XIII) inaccordance with the reaction scheme as shown above. These reactions maybe carried out according to the method disclosed in Japanese PatentApplication Laid-Open (Kokai) 3(1991)-27382.

In any one of the Production Processes A to H, when the substituent Y,Z, or the substituent on R is a reactive group such as hydroxyl group,amino group, carboxyl group, or hydrazono group, such group may beadequately protected during the reaction process with a protectivegroup, which may be removed at the final stage of the reaction. Themethod of introducing and removing the protective group may vary inaccordance with the type of the group to be protected and the protectivegroup used. Such protection may be carried out, for example, by theprocess described in T. W. Green, "Protective Groups in OrganicSynthesis", 1981, Wiley Company.

The protective groups which may be used to protect the hydroxyl group orthe carboxyl group include lower alkyl groups such as methyl group,ethyl group, and t-butyl group; and aralkyl groups such as benzyl groupand 4-nitrobenzyl group, among which the lower alkyl group beingpreferred in view of handling convenience and reactivity. The protectivegroups which may be used to protect the amino group or the hydrazonogroup include trityl group, tosyl group, mesyl group, formyl group,chloroacetyl group, and t-butoxycarbonyl group.

Processes for Producing the Compound of Formula (II)

The compound of formula (II) which is an intermediate in the synthesisof the compound of formula (I) may be synthesized by the process asdescribed below. ##STR10##

When X¹ -X² ˜C˜X³ is CH--N--C═C in formula (II), the compound of formula(II) may be produced by using 5,6,7,8-tetrahydroqinolin-5-one, which isa known compound, for the starting material, and subjecting the5,6,7,8-tetrahydroqinolin-5-one to the reaction process in accordancewith the Production Process D or E. (Production Processes I and J)

When X¹ -X² ˜C˜X³ is N--C═C--N in formula (II), the compound of formula(II) may be produced by using 8-amino-2,3-dihydro-4(1H)-quinolinone,which is a known compound, for the starting material, and subjecting the8-amino-2,3-dihydro-4(1H)-quinolinone to the reaction process inaccordance with any one of the Production Processes F to H. (ProductionProcess K)

The compound of formula (V) and the compound of formula (XII) may beproduced by using 5,6,7,8-tetrahydroqinolin-5-one and8-amino-2,3-dihydro-4(1H)-quinolinone, which are known compounds,respectively, and chemically modifying the ketone group in accordancewith the above-described any one of the Production Processes A to C. Theamino group of the 8-amino-2,3-dihydro-4(1H)-quinolinone may bepreliminarily protected with a protective group for amino group asdescribed above for any one of the Production Processes D to H.

The optical isomer of the compound of formula (I) may be asymmetricallysynthesized by a known method. When Y is hydrogen atom, and Z ishydroxyl group, the ketone derivative of formula (II) may be readilyconverted into an optically active alcohol derivative by the action ofan optically active organic boron reagent or a Baker's Yeast.Alternatively, the ketone derivative of formula (II) may be convertedinto an oxime derivative as described above, and then, converted into anoptically active amino derivative, for example, by asymmetricalreduction in the presence a rhodium catalyst. It is also possible toobtain such optically active derivatives by optical resolution accordingto a known method. These methods of optical isomer production aredescribed in such documents as "Fusei-gosei to kougaku-bunkatsu noshinpo (Progress in asymmetrical synthesis and optical resolution)"(edited by Otsuka and Mukaiyama, 1982, Extra issue of Kagaku, 97,Kagaku-Dojin Shuppan) and "Kou-sentakuteki hannou (Highly selectivereactions)" (edited by Nozaki, Mukaiyama and Nozoe, 1981, Extra issue ofKagaku, 91, Kagaku-Dojin Shuppan), and the optical isomers may beproduced by referring to such documents.

The therapeutic agent for allergic diseases of the present invention iscapable of inhibiting the production of IgE antibody, and accordingly,it may be etiotropically used for the prevention of allergic diseases,prevention of the manifestation of the allergic conditions, preventionof exacerbation of the conditions, and amelioration and cure of theconditions. The allergic diseases that may be prevented or treated bythe therapeutic agent of the present invention include allergic diseasesmediated by IgE antibody, such as bronchial asthma, hay fever,angioneurotic edema, urticaria, serous tympanitis, atopic dermatitis,pollinosis, allergic rhinitis, allergic gastroenteritis, food allergy,drug allergy, and the like.

Next, pharmacological activity, toxicity, way and dose of theadministration, and the like are described with regard to the typicalcompounds of the present invention by referring to the followingexperiments.

Experiment 1 Activity to Inhibit the IgE Antibody Production in Mice

Groups of five male BALB/c mice (body weight: 20 to 25 g) each weresensitized by intraperitoneally injection with 4 mg of aluminumhydroxide to which absorbed 10 μg of egg albumin. The test compound issuspended in a gum arabic solution, and the suspensions of differentconcentrations were orally administered to the animals once a day forseven times in total from immediately after the sensitization. The gumarabic suspension having no test compound added was used for thecontrol.

Blood was collected from the animal ten days after the sensitization,and the collected blood was evaluated for the amount of the IgE antibodyproduced by ELISA. In brief, the plasma sample was added to immobilizedanti-mouse igE antibody, and then, reacting with the anti-mouse IgEantibody having labeled with horseradish peroxidase. The amount of theIgE antibody produced was calculated by using the activity of thehorseradish peroxidase for the index (See Meneki-to-Shikkan (Immune andDiseases), 15, 211-216, 1988).

Compounds Tested

Example 3: 1- (4-chlorophenyl)-8,9-dihydro-7H-pyrrolo-[3,2,1-ij]quinoline;

Example 4: 1- (4-bromophenyl) -8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinolin-7-one hydrazone;

Example 7:7-amino-1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinoline;

Example 9:1-(4-chlorophenyl)-8,9-dihydro-7-methylene-7H-pyrrolo[3,2,1-ij]quinoline;

Example 15: 2-(4-chlorophenyl)-4,5-dihydro-6H-imidazo-[4,5, 1-ij]quinolin-6-one hydrazone;

Example 16:2-(4-chlorophenyl)-4,5-dihydro-6-methoxyimino-6H-imidazo[4,5,1-ij]quinoline;

Example 71:6-amino-4,5-dihydro-2-(4-trifluoromethylphenyl)-imidazo[4,5,1-ij]quinoline;

Example 81:8,9-dihydro-1-(4-trifluoromethylphenyl)-7H-pyrrolo[3,2,1-ij]quinolin-7-one;

Example 92:8,9-dihydro-1-(4-trifluoromethylphenyl)-7H-pyrrolo[3,2,1-ij]quinolin-7-oneoxi;

Example 99:8,9-dihydro-1-(4-fluorophenyl)-7H-pyrrolo-[3,2,1-ij]quinoline;

Example 100:1-(4-bromophenyl)-8,9-dihydro-7H-pyrrolo-[3,2,1-ij]quinoline;

Example 108: 8,9-dihydro-1- (2-naphthyl)-7H-pyrrolo[3,2,1-ij]quinoline;

Example 109:8,9-dihydro-1-(4-methylphenyl)-7H-pyrrolo-[3,2,1-ij]quinoline;

Example 117:1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo-[3,2,1-ij]quinolin-7-onehydrazone;

Example 124:1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo-[3,2,1-ij]quinolin-7-oneisopropylidenehydrazone;

Example 130:8,9-dihydro-1-(4-trifluoromethylphenyl)-7H-pyrrolo[3,2,1-ij]quinoline;

Example 132:7-amino-8,9-dihydro-1-(4-trifluoromethylphenyl)-7H-pyrrolo[3,2,1-ij]quinoline;

Reference Example 30:2-phenyl-4,5-dihydro-6H-imidazo-[4,5,1-ij]quinolin-6-one oxime;

Reference Example 33:2-(4-bromophenyl)-4,5-dihydro-6H-imidazo[4,5,1-ij]quinolin-6-one oxime;

Reference Example 34:2-(4-trifluoromethylphenyl)-4,5-dihydro-6H-imidazo[4,5,1-ij]quinolin-6-oneoxime;

Reference Example 36:2-(2-naphthyl)-4,5-dihydro-6H-imidazo[4,5,1-ij]quinolin-6-one oxime.

In Table 1, there are shown the amount of the test compoundsadministered and the percentage of the IgE antibody production inhibitedcalculated by equation 1: ##EQU1##

                  TABLE 1                                                         ______________________________________                                                                  Percentage of the IgE                                              Dose       antibody production                                 Test Compound  (mg/kg/day)                                                                              inhibited (%)                                       ______________________________________                                        (Example No.)                                                                  3              3         64                                                   4             30         47                                                   7             10         49                                                   9             10         65                                                  15             30         53                                                  16             30         54                                                  71             30         78                                                  81             30         61                                                  92             30         50                                                  99              3         43                                                  100            10         77                                                  108            10         71                                                  109            10         45                                                  117            30         44                                                  124            30         45                                                  130            30         86                                                  132            30         80                                                  (Reference Example No.)                                                       30             30         32                                                  33             30         41                                                  34             30         32                                                  36             30         50                                                  ______________________________________                                    

All of the compounds of the present invention exhibited significantinhibition of the IgE antibody production in BALB/c mice sensitized byegg albumin.

Experiment 2 Activity to Suppress the Histamine Release

Peritoneal cells were collected from male Wistar rats (9 week-old)killed by exsanguination. The cells were washed by centrifugation, andpassively sensitized with rat anti-egg albumin serum. 2×10⁴ of thesensitized peritoneal cells (1×10⁴ of the sensitized peritoneal cells inthe case of the compound of Example 12) were reacted with the solutionof the test compound (in 0.1% bovine serum albumin solution in HBSS(Hanks' balanced salt solution) containing 0.1% DMSO). Egg albumin wasadded as allergen, the reaction was allowed to take place for tenminutes. After the cease of the reaction, the amount of the histaminereleased was determined by post-column fluorometric assay usinghigh-speed liquid chromatography.

The amount of the test compounds administered and the percentage of thehistamine release suppressed calculated by equation 2 are shown in Table2.

Compounds Tested

Example 4:1-(4-bromophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinolin-7-onehydrazone;

Example 12:2-(4-chlorophenyl)-4,5-dihydro-6-hydroxy-6H-imidazo[4,5,1-ij]quinoline;

Example 14:2-(4-chlorophenyl)-4,5-dihydro-6H-imidazo-[4,5,1-ij]quinolin-6-oneisopropylidenehydrazone;

Example 15:2-(4-chlorophenyl)-4,5-dihydro-6H-imidazo-[4,5,1-ij]quinolin-6-onehydrazone;

Example 17:2-(4-chlorophenyl)-4,5-dihydro-6H-imidazo-[4,5,1-ij]quinolin-6-onephenylhydrazone;

Example 117:1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo-[3,2,1-ij]quinolin-7-onehydrazone;

Example 119:1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo-[3,2,1-ij]quinolin-7-onephenylhydrazone;

Example 122:1-(4-chlorophenyl)-8,9-dihydro-7-ethoxyoxalylamino-7H-pyrrolo[3,2,1-ij]quinoline;

Example 123:1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo-[3,2,1-ij]quinolin-7-onetosylhydrazone. ##EQU2##

                  TABLE 2                                                         ______________________________________                                                                Percentage of the                                     Test Compound  Dose     histamine release                                     (Example No.)  (μg/ml)                                                                             suppressed (%)                                        ______________________________________                                         4             10       50                                                     12            10       49                                                     14             3       55                                                     15             1       42                                                     17             3       40                                                    117            10       47                                                    119             3       42                                                    122            10       98                                                    123             3       33                                                    ______________________________________                                    

All of the compounds were found to suppress the release of the histaminefrom the passively sensitized rat peritoneal cells.

Experiment 3 Experiments on Acute Toxicity

To groups of three mice each having a body weight of 20 to 30 g wereorally administered 1000 mg/kg of the compounds of Examples 15 and 117of the present invention. The mice were observed for 7 days after theadministration, and no mouse was found dead.

The above-described results reveal that the compounds of the presentinvention are capable of highly inhibiting the IgE antibody productionfor a prolonged period in experimental animals sensitized with eggalbumin. It was also noted that the antibody production-inhibitingactivity was highly selective to give little influence to the productionof other immunoglobulins. In addition, the compounds of the presentinvention are in vitro capable of highly suppressing the histaminerelease by antigen stimulation from the sensitized mast cells. Furtherthe compounds of the present invention exhibitbroncho-constriction-suppressing activity in an animal activelysensitized with egg albumin. The compounds of the present invention alsohave a very low toxicity, and are highly safe. Accordingly, thecompounds of the present invention are quite useful as an etiotropicalprophylactic and therapeutic agent for various allergic diseasesmediated by IgE antibody such as bronchial asthma, conjunctivitis,rhinitis, dermarls, hypersensitivity, and other allergic diseases, andin particular, as a therapeutic agent for bronchial asthma. In thecuring or prevention of such allergic diseases, the compounds of thepresent invention may be simultaneously used with another conventionaltherapeutic agents for allergic diseases.

The compounds of the present invention can be formulated in the form ofa pharmaceutically acceptable salt, for example, a salt with a mineralacid such as hydrochloric acid, hydrobromic acid, phosphoric acid, orsulfuric acid; a salt with an organic acid such as oxalic acid, citricacid, tartaric acid, maleic acid, alginic acid, p-toluenesulfonic acid,or salicylic acid; an inorganic salt with an alkaline or an alkalineearth metal such as sodium, potassium or calcium; a salt with an organicbase such as triethylamine or pyridine; and a salt with amino acids suchas glutamic acid or aspartic acid.

The compounds of the present invention or salts thereof may beadministered alone. However, they may be formulated into a suitablemedical preparation by adequately combining with a commonly usedsuitable carrier or additive such as exipient, binder, lubricant,coloring agent, or flavoring agent; and if desired, with sterilizedwater, vegetable oil, or other physiologically acceptable solvent orsolubilizer such as ethanol, glycerin, propylene glycol, sorbitol orother polyvalent alcohols; and further with emulsifying or suspendingagent such as Tween 80 or gum arabic; or the like.

The therapeutic agent of the present invention may generally beadministered perorally, but it may be non-orally administered byintravenous, intramuscular, subcutaneous, or intrarectal administration,or by percutaneously or permucosally absorption.

The dose of the therapeutic agent of the present invention may be a dosesufficient to improve the allergic diseases treated, which may differ bythe dosage form, way of administration, frequency of the administrationper day, seriousness of the conditions, body weight, age, and the like.It is generally desirable to use a dose of 0.1 to 5,000 mg/day, andpreferably, a dose of 1 to 500 mg/day.

The dosage form that may be employed include capsule, pill, tablet,granules, grains, powder; as well as internally used solutions such assuspension, emulsion, lemonade, elixir, and syrup; externally appliedsolutions such as inhalant, aerosol, and embrocation; solutions for eyedrop and nasal drop; poultice, ointment, lotion, liniment, epithem,suppository; aqueous and non-aqueous injections; injections in the formof emulsion and suspension; and injections in the form of solid which isto be dissolved, emulsified or suspended upon its use.

EXAMPLES

This invention will be explained in detail with examples and Referenceexamples below but is not deemed to be limited thereof. IR (infra redabsorption) was measured with KBr pellets or thin film (indicated as"neat") and the values were given in cm⁻¹. NMR was measured at 90 MHz or270 MHz (marked with *) of nuclear magnetic resonance at ambienttemperature and the values were given in ppm from TMS(tetramethylsilane) as internal standard. As the solvents, CDCl₃ meansdeuteriated chloroform and DMSO-d₆ means deuteriated dimethyl sulfoxide.A multiplicity of signals is designated as follows, s means singlet, dmeans doublet, t means triplet, q means quartet, dd means doublet ofdoublet, ddd means doublet of doublet of doublet, tt means triplet oftriplet, m means multiplet, brs means broad singlet, and br means broadsignal. An integral of signal is expressed in parenthesis.

Reference Example 1

Preparation of2-(4-chlorophenyl)-4,5-dihydro-6H-imidazo[4,5,1-ij]quinolin-6-one

A mixture of 8-amino-2,3-dihydro-4-(1H)-quinolinone (40 g) , trimethyl4-chloroorthobenzoate (58.8 g) and p-toluenesulfonic acid (4.7 g) wasrefluxed in 400 ml of toluene for 1 hour. The reaction mixture wascooled to the room temperature the brown residue that obtained byconcentration of brown reaction mixture under reduced pressure waspurified by column chromatography, and the title compound was obtainedas colorless needles (45 g).

m.p.: 181.9°-184.6° C.

IR: 1685, 1606, 1465, 1406, 1310, 1281, 1262, 1218, 1093, 1011, 842

NMR (DMSO-d₆): 8.0-7.3 m (7H) , 4.8 ddd (2H) , 3.1 ddd (2H)

Reference Example 2

Preparation of2-(4-chlorophenyl)-4,5-dihydro-6H-imidazo[4,5,1-ij]quinolin-6-one oxime

A mixture of2-(4-chlorophenyl)-4,5-dihydro-6H-imidazo[4,5,1-ij]quinolin-6-one (10g), which was obtained in reference example 1, hydroxylaminehydrochloride (5.6 g), and pyridine (6.5 ml) was stirred in 100 ml ofethanol at room temperature for 2 hours. The colorless crystals werecollected by filtration and washed with ethanol (200 ml). The titlecompound was obtained as colorless crystals (10 g).

m.p.: 203.2°-204.6° C.

IR: 3184, 3161, 1600, 1479, 1448, 1099, 1012, 835, 747

NMR (DMSO-d₆): 12.0 brs (1H), 8.5-7.4 m (7H), 4.6 t (2H), 3.2 t (2H)

Ketones (Reference examples 3 to 28) listed in Table 3 were preparedaccording to the production process described in the reference example 1(Production Process K).

Oximes (Reference examples 29 to 38 ) listed in Table 4 were preparedaccording to the production process described in the reference example 2(Production Process B).

                                      TABLE 3                                     __________________________________________________________________________     ##STR11##                                                                    Reference                                                                     Example                                                                             Y, Z                                                                             R              IR KBr                                                                              NMR ppm    mp °C.                        __________________________________________________________________________     3    O                                                                                 ##STR12##     1689, 1609, 1604, 1465, 1414, 1237, 1164                                            DMSO-d6: 8.2-7.8m(3H), 7.7- 7.3m(4H),                                         4.8t(2H), 3.1t(2H)                                                                       153.4-159.0                           4    O                                                                                 ##STR13##     1689, 1476, 1444, 1346, 700, 693                                                    CDCl3: 8.0dd(1H), 7.9-7.5 m(6H), 7.4dd(1H),                                   .7t(2H), 3.1t(2H)                                                                        115.3-117.3                           5    O                                                                                 ##STR14##     1685, 1654 1606, 1464 1459, 1349 1311,                                              CDCl3: 8.0d(1H), 7.8-7.5m (5H), 7.4dd(1H),                                    4.7t(2H), 3.1t(2H)                                                                       183.8-185.4                           6    O                                                                                 ##STR15##     1685, 1606 1497, 1475, 1363, 1347, 1303, 1274,                                756   CDCl3: 8.3s(1H), 8.1-7.5m (8H), 7.4dd(1H),                                    4.8t(2H), 3.1t(2H)                                                                       144.4-150.5                           7    O                                                                                 ##STR16##     1685, 1609, 1465, 1348, 1268, 1198                                                  CDCl3: 8.0-7.6m(4H), 7.3t (1H), 6.8d(2H),                                     4.7 t(2H), 3.4q(4H), 3.1t(2H),                                                           161.7-164.1                           8    O                                                                                 ##STR17##     1682, 1603 1468, 1342, 1265, 802                                                    CDCl3: 8.2-7.7m(4H), 7.7- 7.2m(3H),                                           4.7t(2H), 3.1t(2H), 2.5s(3H)                                                             155.3-162.7                           9    O                                                                                 ##STR18##     2960, 1686, 1601, 1468, 1346, 1282, 1107, 847,                                800, 752                                                                            CDCl3: 8.1-7.6m(4H), 7.5- 7.2m(3H),                                           4.7t(2H), 3.2-2.8m(1H), 3.1t (2H),                                                       101.3-103.1                          10    O                                                                                 ##STR19##     2953, 2926, 2854, 1697, 1601, 1464, 1346, 1103,                               800, 754                                                                            CDCl3: 8.1-7.6m(4H), 7.5- 7.0m(3H),                                           4.7t(2H), 3.1t(2H), 2.8-2.4m (2H),                                            2.0-0.8m(11H)                                                                            156.3-160.5                          11    O                                                                                 ##STR20##     1686, 1599, 1520, 1348, 1311, 1107, 710                                             DMSO-d6: 8.4d(2H), 8.3d(2H), 8.0d(1H),                                        7.6d(1H), 7.4t(1H), 4.8t (2H),                                                           248.2-254.5                          12    O                                                                                 ##STR21##     1693, 1325, 1174, 1109, 1084, 1066, 752                                             CDCl3: 8.1-7.7m(6H), 7.4t (1H), 4.7t(2H),                                     3.2t (2H)  134.9-147.3                          13    O                                                                                 ##STR22##     1682, 1605, 1477, 1429, 1348, 1309, 1109, 777,                                754   CDCl3: 8.0dd(1H), 7.9-7.2 m(6H), 4.7t(2H),                                    3.1t(2H)   137.9-139.9                          14    O                                                                                 ##STR23##     1674, 1606, 1479, 1439, 1348, 1311, 779,                                            CDCl3: 8.0dd(1H), 7.8dd (1H), 7.7-7.4m                                        (4H), 7.4t(1H), 4.5t (2H),                                                               168.6-171.0                          15    O                                                                                 ##STR24##     1684, 1603, 1450, 1406, 1344, 1308, 1277,                                           CDCl3: 8.1-7.8m(2H), 7.8 dd(1H), 7.8-7.5m                                     (2H), 7.4t(1H), 4.7t (2H),                                                               207.4-210.2                          16    O                                                                                 ##STR25##     1682, 1601, 1471, 1458, 1381, 1348, 1311, 1107,                               800   CDCl3: 8.0dd(1H), 7.8dd (1H), 7.7-7.4m                                        (3H), 7.4t(1H), 4.5t (2H),                                                               154.0-155.0                          17    O                                                                                 ##STR26##     1687, 1603, 1462, 1400, 1346, 1309, 1005, 798,                                750   CDCl3: 8.1-7.8m(3H), 7.8 dd(1H), 7.6d(2H),                                    7.4t(1H), 4.7t (2H), 3.1t(2H)                                                            75.9-89.2                            18    O                                                                                 ##STR27##     2226, 1689, 1605, 1479, 1458, 1412, 1350, 1282,                               1107  CDCl3: 8.1-7.7m(6H), 7.4t (1H), 4.8t(2H),                                     3.2t (2H)  148.9-149.8                          19    O                                                                                 ##STR28##     3398, 1691, 1605, 1479, 1452, 1350, 1313, 1284,                               1109, 854                                                                           DMSO-d6: 8.3s(4H), 8.0d (1H), 7.7d(1H), 7.4                                   (1H), 4.9t(2H), 3.1 t(2H)                                                                180-(dec.)                           20    O                                                                                 ##STR29##     1684, 1603, 1475, 1456, 1261                                                        DMSO-d6: 10.0s(1H), 8.0-7.7 m(3H),                                            7.5d(1H), 7.3t(1H), 7.0d (2H), 4.7t(2H),                                      3.1t (2H)  275.3-278.0                          21    O                                                                                 ##STR30##     3385, 1689, 1605, 1284, 1238                                                        DMSO-d6: 8.1s(4H), 8.0d (1H), 7.6d(1H), 7.4                                   (1H), 4.8t(2H), 3.1 t(2H)                                                                250.7-(dec.)                         22    O                                                                                 ##STR31##     1689, 1606, 1464, 1416, 1257, 1207, 1161                                            CDCl3: 8.0-7.8m(3H), 7.8 dd(1H), 7.5-7.2m                                     (3H), 4.7t(2H), 3.1t (2H)                                                                96.7-97.7                            23    O                                                                                 ##STR32##     1767, 1686, 1601, 1468, 1414, 1346, 1311, 1194,                               1171, 908, 812                                                                      CDCl3: 8.0-7.7m(4H), 7.5- 7.2m(3H),                                           4.7t(2H), 3.1t(2H), 2.3s(3H)                                                             168.4-170.5                          24    O                                                                                 ##STR33##     1713, 1680, 1606, 1286, 1109                                                        CDCl3: 8.3-7.7m(6H), 7.4t (1H), 4.8t(2H),                                     4.0 s(3H), 3.2t(2H)                                                                      198.0-199.2                          25    O                                                                                 ##STR34##     1689, 1605, 1585, 1489, 1464, 1242                                                  CDCl3: 8.1-7.6m(4H), 7.6- 6.9m(8H),                                           4.7t(2H), 3.1t(2H)                                                                       187.8-191.1                          26    O                                                                                 ##STR35##     1676, 1605, 1479, 1441, 1348, 1313, 779,                                            CDCl3: 8.0dd(1H), 7.9-7.3 m(6H), 4.5t(2H),                                    3.1t(2H)   178.0-179.0                          27    O                                                                                 ##STR36##     1687, 1601, 1479, 1444, 1315, 1128, 777                                             CDCl3: 8.1-7.5m(6H), 7.4t (1H), 4.3t(2H),                                     3.1t (2H)  145.2-146.1                          28    O                                                                                 ##STR37##     1686, 1610, 1477, 1259, 1180, 1117, 1103,                                           *DMSO-d6: 7.97d(2H), 7.96d (1H), 7.6d(1H),                                    7.4 t(1H), 7.3d(2H), 6.7tt(1H), 4.8t (2H),                                    4.7t(2H), 3.1t (2H)                                                                      220.5-221.8                          __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________     ##STR38##                                                                    Reference                                                                     Example                                                                             Y, Z R          IR KBr                                                                              NMR ppm    mp °C.                          __________________________________________________________________________    29    NOH                                                                                 ##STR39## 1608, 1493, 1482, 1449, 1165, 1026, 843                                             DMSO-d6: 12.0s(1H), 8.3-7.4 m(7H), 4.6t(2H),                                  3.3 t(2H)  245.7-250.7                            30    NOH                                                                                 ##STR40## 1488, 1479, 1455, 1429, 1014, 796, 754,                                             DMSO-d6: 12.0s(1H), 8.2-7.5 m(8H), 4.7t(2H),                                  3.3t(2H)   240.0-243.4                            31    NOH                                                                                 ##STR41## 3149, 3037, 2843, 1398, 1317, 1174, 1128, 1115,                                     DMSO-d6: 11.5s(1H), 8.1-7.5 m(6H), 7.3t(1H),                                  4.1t(2H), 3.1t(2H)                                                                       270.7-(dec.)                           32    NOH                                                                                 ##STR42## 3115, 3045, 1595, 1483, 1448, 1358, 1169,                                           *DMSO-d6: 11.9s(1H), 8.0-7.6 m(6H), 7.6t(1H),                                 .3t(2H), 3.2t(2H)                                                                        272.3-(dec.)                           33    NOH                                                                                 ##STR43## 3138, 1597, 1477, 1446, 1022, 748                                                   *DMSO-d6: 11.9s(1H), 8.0s (4H), 7.83d(1H),                                    7.76d(1H), 7.6t (1H), 4.6t(2H),                                                          243.4-245.4                            34    NOH                                                                                 ##STR44## 3170, 3062, 2873, 1620, 1419, 1325, 1171,                                           *DMSO-d6: 11.7s(1H), 8.2d (2H), 8.0d(2H),                                     7.8d (1H), 7.6d(1H), 7.4 t(1H), 4.6t(2H), 3.2                                 (2H)       232.6-234.1                            35    NOH                                                                                 ##STR45## 3433, 1468, 1421, 1269, 1211, 1174, 949                                             *DMSO-d6: 11.5s(1H), 8.1d (2H), 7.7d(1H),                                     7.6d (2H), 7.5d(1H), 7.3 t(1H), 4.5t(2H), 3.2                                 (2H)       242.2-244.2                            36    NOH                                                                                 ##STR46## 3433, 1626, 1500, 1475, 1394, 1313                                                  *DMSO-d6: 11.5s(1H), 8.5s (1H), 8.1-8.0m                                      (4H), 7.8-7.5m (4H), 7.3t(1H), 4.7t (2H),                                     3.2t(2H)   239.1-241.2                            37    NOH                                                                                 ##STR47## 3439, 3161, 1599, 1485, 1439, 1165, 1026                                            *DMSO-d6: 11.9s(1H), 7.9-7.6 m(6H), 7.6t(1H),                                 .3t(2H), 3.2t(2H)                                                                        290.8-(dec.)                           38    NOH                                                                                 ##STR48## 3192, 1610, 1493, 1448, 1257, 1186, 1107,                                           *DMSO-d6: 12.0s(1H), 8.0d (2H), 7.82d(1H),                                    7.77d(1H), 7.6t (1H), 7.4d(2H), 6.8 tt(1H),                                   4.8t(2H), 4.6t(2H), 3.3t(2H)                                                             194.1-210.6                            __________________________________________________________________________

EXAMPLE 1 Preparation of1-(4-bromophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinolin-7-one

5,6,7,8-Tetrahydroquinolin-5-one (20 g) was dissolved in 500 ml oftoluene. To this solution was added 4-bromophenacyl bromide (37.8 g)gradually and refluxed for 18 hours. The reaction mixture was cooled toroom temperature, and depositing solids were collected by filtration (33g). These crystals were dissolved in 300 ml of N,N-dimethylformamide. Tothis solution was added, molecular sieves 3A (15 g) and triethylamine(13 ml), and the reaction mixture was heated at 100 ° C. for 1 hour. Thereaction mixture became dark brown. The dark brown solution thatobtained after removing insoluble matter by filtration was concentratedunder reduced pressure. To the residue was added 300 ml of water andextracted with 200 ml of methylene chloride three times. The methylenechloride solution was washed with 100 ml of brine and dried overanhydrous sodium sulfate. The dark brown solution that obtained afterremoving drying agent by filtration was concentrated under reducedpressure, the resultant dark brown residue was purified by aluminacolumn chromatography. The title compound was obtained as dark browncrystals (12 g).

m.p.: 167.8°-170.4° C.

IR: 1654, 1509, 1382, 1273, 1226, 1101, 1008, 834, 727

NMR (CDCl₃): 8.0 dd (1H), 7.6-7.4 m (5H), 7.1 d (1H), 6.5 t (1H), 3.4ddd (2H), 3.0 ddd (2H)

EXAMPLE 2 Preparation of1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinolin-7-one

5,6,7,8-Tetrahydroquinolin-5-one (35 g) was dissolved in 80 ml oftoluene. To this solution was added 4-chlorophenacyl bromide (55.6 g)gradually and refluxed for 18 hours. The reaction mixture was cooled toroom temperature, and depositing crystals were collected by filtration(78 g). These solids were dissolved in 700 ml of N,N-dimethylformamide.To this solution was added, molecular sieves 3A (30 g) and triethylamine(34 ml), then the reaction mixture was heated at 100° C. for 1 hour. Thereaction mixture became dark brown. The dark brown solution thatobtained after removing insoluble matter by filtration was concentratedunder reduced pressure. To the residue was added 300 ml of water, andextracted with 200 ml of methylene chloride three times. This methylenechloride solution was washed with 100 ml of brine and dried overanhydrous sodium sulfate. The dark brown solution that obtained afterremoving drying agent by filtration was concentrated under reducedpressure, the resultant dark brown residue was purified by aluminacolumn chromatography. The title compound was obtained as dark redcrystals (29 g).

m.p.: 153.4°-157.2° C.

IR: 2360, 1683, 1535, 1514, 1471, 1448, 1400, 1384, 1271 264, 1229,1089, 8365

NMR(CDCl₃): 8.0 d (1H), 7.6-7.4 m (5H), 7.1 d (1H), 6.6 t (1H), 3.3 t(2H) , 3.0 t (2H)

EXAMPLE 3 Preparation of1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinolin

5,6,7,8-Tetrahydroquinoline (35 g) was dissolved in 500 ml of toluene.To this solution was added 4-chlorophenacyl bromide (61.4 g) graduallyand refluxed for 1 hour. The reaction mixture was cooled to roomtemperature, and depositing crystals were collected by filtration (86g). These solids were dissolved in 500 ml of N,N-dimethylformamide. Tothis solution was added, molecular sieves 3A (50 g) and triethylamine(44 ml), then the reaction mixture was heated at 100° C. for 1 hour. Thereaction mixture became dark brown. The dark brown solution thatobtained after removing insoluble matter by filtration was concentratedunder reduced pressure. The resultant brown solids were recrystallizedfrom ethanol (300 ml), and the title compound was obtained as colorlessleaflets (50 g).

m.p.: 130.8°-131.1° C.

IR: 2947, 2931, 2917, 2900, 2893, 1515, 1452, 1091, 837, 736

NMR (CDCl₃): 7.7-7.2 m (6H), 6.4 dd (1H), 6.3 d (1H), 3.0 t (2H), 2.8 t(2H), 2.0 tt (2H)

EXAMPLE 4 Preparation of1-(4-bromophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinolin-7-onehydrazone

1-(4-bromophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinolin-7-one (12 g),which was obtained in example 1, was suspended in 100 ml of ethanol. Tothis suspension was added hydrazine monohydrate (3.6 ml) and stirred atroom temperature for 20 hours. The depositing crystals were collected byfiltration and washed with 30 ml of ethanol twice. The title compoundwas obtained as yellow crystals (12 g).

m.p.: 186.5°-189.7° C.

IR: 3194, 3188, 1654, 1637, 1625, 1596, 1533, 1509, 1448, 1440, 1398,1386, 1290, 1226, 1006, 831, 767, 737, 726

NMR (DMSO-d₆): 7.8 d (1H), 7.6-7.3 m (SH), 6.9 d (1H), 6.5 t (1H), 59brs (2H), 3.2 t (2H), 2.8 t (2H)

EXAMPLE 5

Preparation of2-(4-chlorophenyl)-4,5-dihydro-6H-imidazo[4,5,1-ij]quinolin-6-onetosylhydrazone

A mixture of2-(4-chlorophenyl)-4,5-dihydro-6H-imidazo[4,5,1-ij]quinolin-6-one (0.5g), which was obtained in reference example 1, andp-toluenesulfonylhydrazide (0.66 g) was dissolved in 3 ml of ethanol,and stirred at room temperature for 48 hours. The depositing crystalswere collected by filtration and washed with ethanol. The title compoundwas obtained as colorless crystals (0.7 g).

m.p.: 236.8°-237.8° C.

IR: 1464, 1452, 1409, 1374, 1347, 1320, 1183, 1069, 834, 751

NMR (DMSO-d₆): 10.8 brs (1H), 8.0-7.1 m (11H), 4.8 t (2H), 3.1 t (2H),2.4 s (3H)

EXAMPLE 6

Preparation of6-amino-2-(4-chlorophenyl)-4,5-dihydro-6H-imidazo[4,5,1-ij]quinoline

The compound (6 g) obtained in reference example 2 was suspended andhydrogenated in 50 ml of acetic acid and 100 ml of methanol over 10 %Pd/C (0.6 g) at ambient temperature for 8 hours. insoluble matter wasfiltered off with celite, and the filtrate was concentrated underreduced pressure. To the brown residue was added 100 ml of water and thesolution was adjusted to pH 8 with NaHCO₃. This solution was extractedwith methylene chloride (100 ml×3). This organic solution was washedwith brine and dried over anhydrous magnesium sulfate. Removing dryingagent by filtration, and solvent by evaporation under reduced pressureof organic solution and afforded brown residue. This brown residue gaspurified by column chromatography. The title compound was obtained asbrown solid (4.6 g).

m.p.: 141.8°-144.4° C.

IR: 3358, 3030, 2923, 1463, 1365, 1342, 794, 751, 711, 701

NMR (DMSO-d₆): 8.0-7.0 m (7H), 4.5 t (2H), 4.2 dd (1H), 2.4-2.0 m (4H)

EXAMPLE 7

Preparation of7-amino-1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinoline

1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinolin-7-one (10g), which was obtained in example 2, was dissolved in 100 ml of CH₂ Cl₂and 100 ml of methanol at ambient temperature. To this red solution wasadded ammonium acetate (27.4 g) gradually. After stirring for 3 hours atambient temperature, to this solution was added NaBH₃ CN (2.3 g) andstirred for 12 hours at ambient temperature. To this yellow solution wasadded 500 ml of ethyl acetate and extracted with 3N H₂ SO₄ (20 ml×4) aq.This dil. H₂ SO₄ solution was made alkali with 3N NaOH aq., then yellowcrystals were deposited. These crystals were extracted with CH₂ Cl₂ (50ml×4). This organic layer was washed with brine (30 ml×1) and dried overanhydrous sodium sulfate. Removing drying agent by filtration andsolvent by evaporation under reduced pressure of the organic solutionafforded yellow residue. This yellow residue was purified by aluminacolumn chromatography, and the title compound was obtained as yellowcrystals (6 g).

m.p.: 132.0°-135.0° C.

IR: 3421, 1560, 1517, 1509, 1500, 1092, 832, 735

NMR (CDCl₃): 7.7-7.3 m (8H), 6.5-6.4 m (2H), 4.1 dd (2H), 3.1 t (2H),2.2-1.8 m (2H)

EXAMPLE 8

Preparation of1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinolin-7-one oxime

To the solution of1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinolin-7-one (1.93g), which was obtained in example 2, in 40 ml of ethanol was addedhydroxylamine hydrochloride (0.97 g) and pyridine (1.1 ml), then thereaction mixture was stirred for 3 hours at ambient temperature. Aftercondensing the reaction mixture, 100 ml of ethyl acetate was added tothe residue, and washed with water and brine, then the organic layer wasdried over anhydrous sodium sulfate. After removing drying agent byfiltration and solvent by evaporation under reduced pressure, theresidue was precipitated with ethyl acetate and ether, and thecrystaline title compound was liltrated and given (1.07 g).

m.p.: 203.2°-204.6° C.

IR: 3228, 2927, 2899, 1445, 1012, 935, 869, 765, 732

NMR (DMSO-d₆): 11.4 S (1H), 8.1 d (1H), 7.8 S (1H), 7.7-7.4 m (4H), 6.9d (1H), 6.6 dd (1H), 3.2-2.9 m (4H)

EXAMPLE 9

Preparation of1-(4-chlorophenyl)-8,9-dihydro-7-methylene-7H-pyrrolo[3,2,1-ij]quinoline

Methyltriphenylphosphonium bromide (3.8 g) was added to 25 ml ofanhydrous tetrahydrofuran. To this mixture was added the solution ofpotassium t-butoxide (1.2 g) in 25 ml of tetrahydrofuran at ambienttemperature. After stirring for 3 hours, to this solution was added thesolution of1-(4-chlorophenyl)-8,9-dihydro-7H-pyrrolo[3,2,1-ij]quinolin-7-one (1.5g), which was obtained in example 2, in 15 ml of tetrahydrofuran. Afterstirring for 30 min., to this solution was added water and extractedwith ethyl acetate. The organic solution was washed with brine and driedover anhydrous sodium sulfate. After removing drying agent by filtrationand organic solvent by evaporation under reduced pressure, the residuewas purified by alumina column chromatography, and the title compoundwas obtained as yellow crystals (1.1 g) .

m.p.: 125.3°-127.2° C.

IR: 3103, 1513, 1446, 1400, 1093, 833, 741.

NMR (CDCl₃): 7.9-7.2 m (6H), 6.7 d (1H), 6.4 t (1H), 5.6 s (1H), 5.2 s(1H), 3.1 t (2H), 2.8 t (2H).

The production processes of compounds in example 1 to 148 are listed intable 5, and the structures, m.p., IR and NMR datum for the compounds inexamples 10 to 148 are listed in tables 6 to 9.

                  TABLE 5                                                         ______________________________________                                        Production                                                                    Process    Example No.                                                        ______________________________________                                        Process A  4, 10, 14-15, 19-20, 29-32, 34-47, 50, 117,                                   120-121, 124                                                       Process B  5, 8, 13, 16-17, 21-24, 26, 28, 33, 48,                                       51-53, 59, 64-66, 68, 70, 74, 76, 89-97,                                      118-119, 123, 125-126, 128-129, 138, 140,                                     142, 144-147                                                       Process C  6, 7, 9, 11, 12, 18, 25, 27, 49, 54-58,                                       60-63, 67, 69, 71-73, 75, 77, 116, 122,                                       127, 131-137, 139, 141, 143, 148                                   Process D  3, 98-115, 130                                                     Process I  1, 2, 78-88                                                        ______________________________________                                    

                                      TABLE 6                                     __________________________________________________________________________     ##STR49##                                                                    Example                                                                            Y, Z           R              IR KBr   NMR ppm      mp                   __________________________________________________________________________                                                             °C.           10   NNH.sub.2                                                                                     ##STR50##     3357, 1602, 1475, 1449, 1435, 1390,                                           1364, 1313, 1266, 825, 795,                                                            CDC13: 8.3s(1H), 8.1-7.4m                                                     (8H), 7.3dd(1H), 5.5brs(2H),                                                  4.6t (2H), 3.0t(2H)                                                                        195.6-197.4          11   H, H                                                                                          ##STR51##     1459, 1450, 1426, 1411, 1260, 1100,                                           840, 784, 749                                                                          CDC13: 7.8d(2H), 7.7-6.9                                                      m(5H), 4.4t(2H), 3.0t(2H),                                                    2.2tt(2H)    130.1-133.4          12   H, OH                                                                                         ##STR52##     3244, 1464, 1443, 1414, 1115, 1095,                                           836, 755 DMSO-d6: 8.0d(2H), 7.7-7.5                                                    m(3H), 7.3-7.1m (2H),                                                         5.5d(1H), 5.0 dt(1H),                                                         4.5t(2H), 2.5m(2H)                                                                         251.5-255.5          13   NOCH.sub.2 CO.sub.2 H                                                                         ##STR53##     2910, 1718, 1418, 1236, 1224, 1100,                                           1084, 946, 870                                                                         DMSO-d6: 8.0d(2H), 7.8-7.4                                                    m(4H), 7.3dd(1H), 4.7s(2H),                                                   4.5t (2H), 3.3t(2H)                                                                        237.1-242.7          14   NNC(CH.sub.3).sub.2                                                                           ##STR54##     1631, 1621, 1474, 1461, 1350, 1305,                                           1093, 748                                                                              CDCl3: 7.9-7.7m(4H), 7.6-7.5m(                                                3H), 4.5t (2H), 3.3t(2H),                                                     2.15s(3H), 2.08s (3H)                                                                      151.3-153.5          15   NNH.sub.2                                                                                     ##STR55##     3388, 3357, 1462, 1409, 1094, 729,                                                     CDCl3: 8.0-7.1m(7H), 5.5                                                      brs(2H), 4.5t (2H),                                                                        163.6-167.4          16   NOCH.sub.3                                                                                    ##STR56##     1601, 1478, 1446, 1158, 1099, 1045,                                           1032, 834                                                                              DMSO-d6: 8.2-7.4m(7H), 4.6t                                                   (2H), 4.0s(3H), 3.2t(2H)                                                                   177.4-182.0          17                                                                                  ##STR57##                                                                                    ##STR58##     3287, 1600, 1577, 1571, 1496, 1474,                                           1413, 1254, 1163, 751                                                                  DMSO-d6: 9.7brs(1H), 8.1-                                                     6.6m(12H), 4.6t (2H),                                                         3.2t(2H)     127.1-128.3          18   H, NHCOCO.sub.2 C.sub.2 H.sub.5                                                               ##STR59##     1739, 1735, 1700, 1697, 1685, 1542,                                           1465, 1459, 1412, 1214                                                                 CDCl3: 7.9-7.1m(8H), 5.6-5.3m(                                                1H), 4.6-4.2m(2H), 4.4 q(2H),                                                 2.6-2.2m (2H),                                                                             213.9-215.6          19   NNH.sub.2                                                                                     ##STR60##     3342, 3313, 1459, 1446, 1403, 1364,                                           1315, 1008, 829, 747                                                                   CDCl3: 7.9-7.5m(6H), 7.3                                                      t(1H), 5.5brs (2H), 4.5t(2H),                                                 .0t(2H)      186.4-187.8          20   NNH.sub.2                                                                                     ##STR61##     3343, 3185, 2967, 1608, 1466, 1430,                                           1359, 1270, 1198                                                                       CDC13: 7.8-7.4m(4H), 7.2                                                      t(1H), 6.7d(2H), 5.5brs(2H),                                                  4.5t (2H), 3.4q(4H), 2.9t(2H),                                                 1.2t(6H)    165.6-169.4          21                                                                                  ##STR62##                                                                                    ##STR63##     1603, 1592, 1577, 1522, 1449, 1438,                                           1412, 1147, 1092                                                                       DMSO-d6: 10.3brs(1H), 8.2d                                                    (1H), 8.0d(2H), 7.8-7.5m(5H),                                                 7.4 d(1H), 7.3 t(1H),                                                         6.8t(1H), 4.6t (2H),                                                                       177.3-180.8          22                                                                                  ##STR64##                                                                                    ##STR65##     1659, 1656, 1625, 1608, 1479, 1409,                                           1377, 1096, 1066, 741                                                                  DMSO-d6: 11.7brs(1H), 8.9-                                                    8.0br(1H), 8.0- 7.5m(6H),                                                     7.3t (1H), 4.6t(2H), 3.8s(4H),                                                 3.2t (2H)   >300                 23                                                                                  ##STR66##                                                                                    ##STR67##     3221, 2988, 1703, 1529, 1474, 1407,                                           1251, 1241, 1093, 1051                                                                 DMSO-d6: 10.5s(1H), 8.0d                                                      (2H), 7.7-7.4m (4H),                                                          7.3t(1H), 4.5t(2H), 4.2q                                                      (2H), 3.1t(2H), 1.3t(3H)                                                                   219.9-(dec.)         24                                                                                  ##STR68##                                                                                    ##STR69##     1601, 1477, 1467, 1444, 1419, 1099,                                           1057, 1014, 839, 797                                                                   DMSO-d6: 8.0d(2H), 7.9-7.6                                                    m(4H), 7.4t(1H), 5.6s(2H),                                                    4.6t (2H), 3.3t(2H)                                                                        285.2-(dec.)         25                                                                                  ##STR70##                                                                                    ##STR71##     3281, 3060, 2910, 1653, 1641, 1542,                                           1535, 1438, 1409                                                                       DMSO-d6: 7.8d(2H), 7.7d (1H),                                                 7.5d(2H), 7.2 t(1H),                                                          7.1d(1H), 6.6d(1H), 5.5-5.2                                                   m(1H), 4.4t(2H), 3.0-2.5m(4H),                                                 2.4-2.2m(2H),                                                                             215.4-216.7          26                                                                                  ##STR72##                                                                                    ##STR73##     3240, 3100, 1674, 1624, 1593, 1463,                                           1406, 1091                                                                             *DMSO-d6: 11.7brs(1H), 7.9brs                                                 3H), 8.0d(3H), 7.74d(1H),                                                     7.66d (2H), 7.3t(1H),                                                         4.6t(2H), 3.3t(2H)                                                                         284.2-290.4          27   CH.sub.2                                                                                      ##STR74##     1460, 1409, 1096, 890, 837, 829,                                                       CDCl3: 7.9-7.2m(7H), 5.7                                                      brs(1H), 5.2brs (1H),                                                         4.4t(2H), 3.0t(2H)                                                                         110.3-111.0          28                                                                                  ##STR75##                                                                                    ##STR76##     3471, 1695, 1577, 1464, 1459, 1408,                                           1093     DMSO-d6: 9.8brs(1H), 8.0d                                                     (2H), 7.8d(1H), 7.6 d(3H),                                                    7.2t(1H), 6.6brs(2H), 4.5t                                                    (2H), 3.1t(2H)                                                                             248.5-250.1          29   NNH.sub.2                                                                                     ##STR77##     3192, 1608, 1470, 1416, 1221, 1157,                                           849      CDCl3: 8.0-7.5m(4H), 7.4-                                                     7.2m(3H), 5.5brs (2H),                                                        4.5t(2H), 3.0t(2H)                                                                         122.7-127.0          30   NNH.sub.2                                                                                     ##STR78##     3398, 3196, 1616, 1471, 1448, 1319,                                           804, 758 CDCl3: 7.9-7.5m(4H), 7.4-7.2m(                                                3H), 4.5 t(2H), 3.0t(2H),                                                     2.4s(3H)     150-(dec.)           31   NNH.sub.2                                                                                     ##STR79##     3194, 2956, 1614, 1468, 1448, 1419,                                           806, 758 CDCl3: 7.9-7.6m(4H), 7.5-7.3m(                                                3H), 5.5 brs(2H), 4.5t (2H),                                                  3.1-2.8m (1H), 3.0t(2H),                                                      1.3d(6H)     176.3-182.1          32   NNH.sub.2                                                                                     ##STR80##     3396, 3192, 2958, 2927, 2854, 1614,                                           1466, 1448, 806, 758                                                                   CDCl3: 8.0-7.6m(4H), 7.5-7.2m(                                                3H), 5.5 brs(2H), 4.5t (2H),                                                  3.0t(2H), 2.7t(2H), 2.0-0.7                                                   m(11H)       156.3-160.5          33   NNHCH.sub.3                                                                                   ##STR81##     2922, 1620, 1606, 1570, 1462, 1406,                                           1095, 750                                                                              CDCl3: 7.8-7.1m(7H), 5.0                                                      brs(1H), 4.5t (2H), 3.2s(3H),                                                 .9t(2H)      118.0-120.7          34   NNH.sub.2                                                                                     ##STR82##     3336, 3172, 1599, 1518, 1344, 856,                                            746, 704 DMSO-d6: 8.4d(2H), 8.2d (2H),                                                 7.7-7.4m (2H), 7.3t(1H),                                                      6.8brs(2H), 4.6t (2H),                                                        3.0t(2H)     215.0-(dec.)         35   NNH.sub.2                                                                                     ##STR83##     3151, 1618, 1417, 1325, 1120, 1066,                                           847, 737 CDCl3: 8.1-7.6m(6H), 7.3t                                                     (1H), 5.5brs(2H), 4.5t(2H),                                                   3.0t(2H)     155.0-(dec.)         36   NNH.sub.2                                                                                     ##STR84##     3336, 3186, 1427, 1319, 785, 748, 731,                                        712      CDCl3: 7.9-7.2m(7H), 5.5                                                      brs(2H), 4.5t (2H),                                                                        151.9-153.4          37   NNH.sub.2                                                                                     ##STR85##     3392, 3217, 1444, 1392, 770,                                                           CDCl3: 7.8-7.2m(7H),                                                          5.5brs(2H), 4.3t(2H),                                                         3.0t(2H)     90.7-93.6            38   NNH.sub.2                                                                                     ##STR86##     3336, 3209, 1452, 1404, 1317, 797,                                                     CDCl3: 8.0d(1H),                                                              7.9-7.4m(4H), 7.3t(1H),                                                       5.5brs(2H), 4.5t (2H),                                                        3.0t(2H)     145.2-149.4          39   NNH.sub.2                                                                                     ##STR87##     3379, 3223, 1443, 1392, 1321, 825,                                            804, 744 CDCl3: 7.8-7.1m(6H),                                                          5.5brs(2H), 4.2t(2H),                                                         3.0t(2H)     206.2-207.7          40   NNH.sub.2                                                                                     ##STR88##     3433, 1647, 1630, 1404, 829, 746,                                                      CDCl3: 7.9d(2H),                                                              7.8-7.5m(2H), 7.6d(2H),                                                       7.3dd(1H), 5.5brs (2H),                                                       4.5t(2H), 3.0t(2H)                                                                         260.7-(dec.)         41   NNH.sub.2                                                                                     ##STR89##     3392, 3190, 1616, 1444, 1423, 1350,                                           748      DMSO-d6: 8.3-7.1m(7H),                                                        4.6t(2H), 3.0t(2H)                                                                         200-(dec.)           42   NNH.sub.2                                                                                     ##STR90##     3325, 3219, 1614, 1475, 1390, 1273,                                           841      DMSO-d6: 7.8d(2H),                                                            7.5-7.3m(2H), 7.1t(1H),                                                       6.9d(2H), 6.6brs (2H),                                                        4.5t(2H), 2.9t(2H)                                                                         185.3-(dec.)         43   NNH.sub.2                                                                                     ##STR91##     3371, 3219, 1591, 1547, 1385,                                                          DMSO-d6: 8.1d(2H), 8.0d(2H),                                                  7.6- 7.3m(2H), 7.2t(1H),                                                      6.7brs (2H), 4.5t(2H),                                                        3.0t(2H)     >300                 44   NNH.sub.2                                                                                     ##STR92##     3151, 1614, 1471, 1263, 1213, 1173,                                           798      CDCl3: 8.0-7.5m(4H), 7.4-7.1m                                                 3H), 5.5brs(2H), 4.5t(2H),                                                    3.0t(2H)     140.1-144.4          45   NNH.sub.2                                                                                     ##STR93##     3359, 3223, 1705, 1608, 1439, 1410,                                           1284, 1115, 706                                                                        CDCl3: 8.2d(2H), 8.0d(2H),                                                    7.8- 7.6m(2H), 7.3t(1H),                                                      5.5brs (2H), 4.6t(2H),                                                        4.0s(3H), 3.0t(2H)                                                                         227.0-(dec.)         46   NNH.sub.2                                                                                     ##STR94##     3379, 3205, 1475, 1441, 1387, 777,                                            743, 710, 700                                                                          CDCl3: 7.8-7.2m(8H),                                                          5.5brs(2H), 4.5t(2H),                                                         3.0t(2H)     151.3-153.8          47   NNH.sub.2                                                                                     ##STR95##     3413, 3167, 1612, 1587, 1489, 1468,                                           1230, 752                                                                              CDCl3: 8.0-7.0m(12H),                                                         5.5brs(2H), 4.5t(2H),                                                         3.0t(2H)     151.0-154.3          48   NN(CH.sub.3).sub.2                                                                            ##STR96##     2862, 1606, 1464, 1408, 1350, 1315,                                           1097, 960, 837, 754                                                                    CDCl3: 7.9-7.7m(4H),                                                          7.5d(2H), 7.3t(1H), 4.5t(2H),                                                 .3t(2H), 2.7s(6H)                                                                          117.7-119.6          49   CHCN                                                                                          ##STR97##     2206, 1593, 1462, 1410, 1356, 1313,                                           1092, 791, 746                                                                         CDCl3: 7.9-7.7m(3H), 7.6-7.3m                                                 3H), 7.3t(1H), 6.0brs(1H),                                                    4.5t(2H), 3.3dt(2H)                                                                        185.4-207.0          50   H, NC(CH.sub.3).sub.2                                                                         ##STR98##     3431, 3059, 2954, 1660, 1458, 1410,                                           1093, 841, 752                                                                         CDCl3: 8.1-6.8m(7H),                                                          5.0t(1H), 4.8-4.3m(2H),                                                       2.5-2.0m (2H), 2.2s(3H),                                                      2.1s(3H)     102.7-124.8          51                                                                                  ##STR99##                                                                                    ##STR100##    2935, 2794, 1462, 1408, 1313, 1095,                                           839, 746 CDCl3: 7.9-7.6m(4H),                                                          7.5d(2H), 7.3t(1H),4.5t(2H),                                                  3.3t (2H), 3.0-2.6m(4H), 1.9-                                                 .3m(6H)      219.9-221.5          52                                                                                  ##STR101##                                                                                   ##STR102##    2821, 1610, 1471, 1408, 1309, 1263,                                           1107, 958, 831                                                                         CDCl3: 7.9-7.6m(4H),                                                          7.5d(2H), 7.3t(1H), 4.5t(2H),                                                 3.9dd (4H), 3.3t(2H),                                                         2.9dd(4H)    211.0-216.7          53                                                                                  ##STR103##                                                                                   ##STR104##    1493, 1462, 1408, 1311, 1169, 1097,                                           1061, 802, 754, 621                                                                    *DMSO-d6: 8.9s(2H),                                                           7.99d(2H), 7.95d (1H),                                                        7.9d(1H), 7.7d(2H), 7.4t(1H),                                                 4.6t(2H), 3.3t(2H)                                                                         229.6-236.0          54                                                                                  ##STR105##                                                                                   ##STR106##    3431, 3400, 2958, 1597, 1477, 1446,                                           1099, 1009, 758                                                                        *DMSO-d6: 10.7brs(1H),                                                        10.4br(1H), 8.4br(3H),                                                        8.0d(2H), 7.9d (1H),                                                          7.8d(2H), 7.7d(1H), 7.6t(1H),                                                 5.1-4.9m(2H), 4.7-4.5m(1H),                                                   3.6-3.2m (3H), 2.9-2.7m(1H),                                                  2.6- 2.4m(2H)                                                                              214.9-215.4          55   CHCH.sub.2 NH.sub.2.HCl                                                                       ##STR107##    3417, 2987, 1616, 1599, 1479, 1448,                                           1385, 1169, 1095, 791                                                                  *DMSO-d6: 8.6-8.3brs(3H),                                                     8.1d(2H), 7.8d(2H), 7.8d(1H),                                                 7.7d (1H), 7.6t(1H),                                                          6.5t(1H), 4.6t(2H),                                                           3.8-3.7m(2H), 3.1t(2H)                                                                     190.9-192.8          56   CHCH.sub.2 NH.sub.2                                                                           ##STR108##    neat: 3396, 1460, 1441, 1410, 1381,                                           1371, 1093, 791, 748                                                                   *DMSO-d6: 8.0d(2H), 7.7d(2H),                                                 7.6d (1H), 7.4d(1H),                                                          7.2t(1H), 6.3t(1H), 4.5t(2H),                                                 3.5d (2H), 2.9t(2H)                                                                        oil                  57   H, CH.sub.2 CH.sub.2 NH.sub.2                                                                 ##STR109##    3421, 3400, 3030, 3014, 2956, 2929,                                           1462, 1414, 1385                                                                       *DMSO-d6: 8.0d(2H),                                                           7.8brs(2H), 7.7d (2H),                                                        7.5d(1H), 7.2t(1H), 7.1d(1H),                                                 4.6-4.4m(2H), 3.3-3.2m(1H),                                                   3.1-2.9m (2H),                                                                             220.0-222.9)         58   H, NHCH.sub.3.HCl                                                                             ##STR110##    3404, 2926, 1470, 1441, 1389, 1342,                                           750, 698 DMSO-d6: 8.0brs(2H),                                                          8.1-7.3m(7H), 4.9-4.5m(3H),                                                   2.8-2.4m(5H) 70.5-75.9            59                                                                                  ##STR111##                                                                                   ##STR112##    2937, 1651, 1512, 1406, 1244, 1093,                                           746      CDC13: 10.1brs(1H),                                                           7.84d(2H), 7.80d(1H),                                                         7.7-7.2m(2H), 7.6s(2H),                                                       7.1d(2H), 6.8d (2H),                                                          4.5t(2H), 3.8s(3H), 3.6-2.9m(5                                                H), 2.9-2.4m (4H),                                                            2.4-1.8m(6H) 243.0-247.1          60   H, CH.sub.2 CN                                                                                ##STR113##    2249, 1464, 1441, 1410, 1342, 833,                                                     *CDCl3: 7.8d(2H), 7.7d(1H),                                                   7.5d (2H), 7.3t(1H),                                                          7.1d(1H), 4.5-4.4m(2H),                                                       3.6-3.5m (1H), 3.0dd(1H),                                                     2.7dd (1H), 2.6-2.5m(1H),                                                     2.3- 2.2m(1H)                                                                              152.2-153.4          61   H, NH.sub.2                                                                                   ##STR114##    1437, 1392, 1315, 1167, 1136, 1111,                                           777      *CDCl3: 7.9dd(1H),                                                            7.7-7.6m(3H), 7.5dd(1H),                                                      7.3-7.2m(2H), 4.5dd(1H),                                                      4.1-3.9m(2H), 2.7 brs(2H),                                                    2.4-2.1m(2H) 139.7-142.6          62                                                                                  ##STR115##                                                                                   ##STR116##    3400, 2956, 2773, 1599, 1479, 1448,                                           1097, 835, 798, 758                                                                    *DMSO-d6: 10.6brs(1H),                                                        10.4brs(1H), 9.3brs(2H),                                                      8.0d(2H), 7.9d (1H),                                                          7.8d(2H), 7.8-7.7m (1H),                                                      7.6t(1H), 5.0-4.8m (2H),                                                      4.7-4.6m(1H), 4.1brs (1H),                                                    3.7-3.6m(4H), 3.6- 3.3m(2H),                                                  3.2-3.0m(2H), 2.9-2.8m(1H),                                                   2.6-2.4m(1H) 171.5-185.4          63   H, NH.sub.2.HCl                                                                               ##STR117##    3431, 2895, 1601, 1439, 1398,                                                          *DMSO-d6: 8.9brs(3H),                                                         7.9d(1H), 7.7d (1H),                                                          7.6-7.5m(4H), 7.3t (1H),                                                      4.2t(1H), 3.4-3.3m (2H),                                                      2.5-2.3m(2H) 197.5-206.3          64   NOCH.sub.3                                                                                    ##STR118##    3433 1477, 1448, 1387, 1319,                                                           *CDCl3: 7.8d(1H),                                                             7.8-7.7m(2H), 7.6dd(1H),                                                      7.5-7.4m(2H), 7.4t(1H),                                                       4.2t(2H), 4.1s (3H),                                                                       89.3-90.4            65   NOCH.sub.3                                                                                    ##STR119##    2939, 1479, 1441, 1387, 1313, 1180,                                           1130, 1053                                                                             *CDCl3: 7.9-7.5m(6H),                                                         7.4t(1H), 4.1s(3H), 4.0t(2H),                                                 3.2t(2H)     175.2-177.3          66   NOCH.sub.3                                                                                    ##STR120##    2935, 1475, 1462, 1406, 1315, 1045,                                           856      *DMSO-d6: 7.9d(2H), 7.8d(2H),                                                 7.7d (1H), 7.5d(1H),                                                          7.3t(1H), 4.5t(2H), 4.0s(3H),                                                 .2t(2H)      195.7-198.2          67   H, NH.sub.2                                                                                   ##STR121##    3375, 3300, 1460, 1408, 1009, 833,                                                     *CDCl3: 7.8d(2H),                                                             7.7-7.6m(1H), 7.7d(2H),                                                       7.3-7.2m(2H), 4.6-4.4m(3H),                                                   2.4-2.0m (2H),                                                                             170.3-172.2H)        68   NOCH.sub.3                                                                                    ##STR122##    1477, 1443, 1383, 1350, 1057, 928,                                                     *CDCl3: 7.9-7.8m(3H),                                                         7.7d(1H), 7.6-7.5m(3H),                                                       7.3t(1H), 4.5t(2H), 4.1s(3H),                                                 3.3t(2H)     82.0-83.1            69   H, NH.sub.2                                                                                   ##STR123##    3359, 1468, 1446, 1389, 1365, 1342,                                           752      *CDCl3: 7.9-7.8m(2H),                                                         7.7dd(1H), 7.6-7.4m(3H),                                                      7.3-7.2m (2H), 4.6-4.4m(3H),                                                  2.4- 2.1m(2H)                                                                              143.6-145.5          70   NOCH.sub.3                                                                                    ##STR124##    2947, 1620, 1475, 1416, 1325, 1165,                                           1124, 1043, 856                                                                        *CDCl3: 8.0d(2H),                                                             7.8-7.7m(4H), 7.7dd(1H),                                                      4.5t(2H), 3.3t(2H)                                                                         140.6-142.1          71   H, NH.sub.2                                                                                   ##STR125##    3433, 1622, 1417, 1327, 1169,                                                          *CDCl3: 8.0d(2H), 7.8d(2H),                                                   7.7dd (1H), 7.3-7.2m(2H),                                                     4.6- 4.4m(3H),                                                                             118.3-120.8)         72   H, NH.sub.2                                                                                   ##STR126##    3431, 1468, 1255, 1215,                                                                *CDCl3: 7.9d(2H),                                                             7.7-7.6m(1H), 7.4d(2H),                                                       7.3-7.2m(2H), 4.6-4.3m(3H),                                                   2.6brs(2H), 2.4-2.1m(2H)                                                                    98.9-100.8          73   H, NH.sub.2                                                                                   ##STR127##    3431, 1624, 1603, 1500, 1433, 1394,                                           754      *CDCl3: 8.3s(1H),                                                             8.0-7.5m(7H), 7.3-7.2m(2H),                                                   4.7-4.4m (3H),                                                                             159.9-161.8)         74   NOCH.sub.3                                                                                    ##STR128##    1608, 1493, 1450, 1269, 1128, 1107,                                           1047     *DMSO-d6: 8.0d(2H), 7.9d(1H),                                                 7.8d (1H), 7.6t(1H),                                                          7.4d(2H), 6.8tt(1H),                                                          4.8t(2H), 4.6t (2H),                                                          4.0s(3H), 3.3t(2H)                                                                         261.3-264.1          75   H, NH.sub.2                                                                                   ##STR129##    3404, 1612, 1462, 1259, 1111, 1093,                                           837      *DMSO-d6: 7.9d(2H), 7.5d(1H),                                                 7.3d (2H), 7.22d(1H),                                                         7.15t(1H), 6.7tt(1H),                                                         4.7t(2H), 4.5t (2H),                                                          4.2dd(1H), 2.3- 1.9m(2H)                                                                   102.9-124.3          76   NNHCHO                                                                                        ##STR130##    3178, 3066, 1693, 1460, 1406, 1348,                                           1261, 1095                                                                             DMSO-d6: 11.4d(1H), 8.8d(1H),                                                 8.2- 7.4m(6H), 7.3t(1H), 4.6t                                                 2H), 3.2t(2H)                                                                              210.0-(dec.)         77                                                                                  ##STR131##                                                                                   ##STR132##    1595, 1462, 1406, 1367, 1194, 1178,                                           1095, 820                                                                              CDCl3: 8.1-7.2m(11H),                                                         4.5t(2H), 3.4t(2H),                                                                        198.7-204.8          __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________     ##STR133##                                                                   Example                                                                            Y, Z                                                                             R          IR, KBr           NMR ppm             mp                   __________________________________________________________________________                                                             °C.           78   O                                                                                 ##STR134##                                                                              1674, 1538, 1451, 1391, 1103, 767, 713                                                           ##STR135##         125.2-127.1          79   O                                                                                 ##STR136##                                                                               ##STR137##                                                                                      ##STR138##         174.6-176.3          80   O                                                                                 ##STR139##                                                                               ##STR140##                                                                                      ##STR141##         161.7-164.8          81   O                                                                                 ##STR142##                                                                               ##STR143##                                                                                      ##STR144##         130.3-131.7          82   O                                                                                 ##STR145##                                                                               ##STR146##                                                                                      ##STR147##         216.2-217.0          83   O                                                                                 ##STR148##                                                                               ##STR149##                                                                                      ##STR150##         141.2-142.8          84   O                                                                                 ##STR151##                                                                               ##STR152##                                                                                      ##STR153##         178.9-180.9          85   O                                                                                 ##STR154##                                                                               ##STR155##                                                                                      ##STR156##         166.2-167.7          86   O                                                                                 ##STR157##                                                                               ##STR158##                                                                                      ##STR159##         142.7-144.8          87   O                                                                                 ##STR160##                                                                              1678, 1279, 1261, 1234, 1207, 1149                                                               ##STR161##         111.5-112.1          88   O                                                                                 ##STR162##                                                                               ##STR163##                                                                                      ##STR164##         194.9-196.5          __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________     ##STR165##                                                                   Example                                                                            Y, Z R          IR, KBr         NMR ppm             mp                   __________________________________________________________________________                                                             °C.           89   NOH                                                                                 ##STR166##                                                                               ##STR167##                                                                                    ##STR168##         192.1-196.4          90   NOH                                                                                 ##STR169##                                                                               ##STR170##                                                                                    ##STR171##         241.6-243.5          91   NOH                                                                                 ##STR172##                                                                               ##STR173##                                                                                    ##STR174##         188.2-189.8          92   NOH                                                                                 ##STR175##                                                                               ##STR176##                                                                                    ##STR177##         214.1-215.3          93   NOH                                                                                 ##STR178##                                                                               ##STR179##                                                                                    ##STR180##         199.8-200.6          94   NOH                                                                                 ##STR181##                                                                               ##STR182##                                                                                    ##STR183##         205.6-207.2          95   NOH                                                                                 ##STR184##                                                                               ##STR185##                                                                                    ##STR186##         192.5-194.7          96   NOH                                                                                 ##STR187##                                                                               ##STR188##                                                                                    ##STR189##         206.1-208.5          97   NOH                                                                                 ##STR190##                                                                              3230, 2931, 1265, 1230, 1211, 1165                                                             ##STR191##         207.5-208.6          __________________________________________________________________________

                                      TABLE 9                                     __________________________________________________________________________     ##STR192##                                                                   Example                                                                            Y, Z        R            IR KBr      NMR ppm        mp                   __________________________________________________________________________                                                             °C.            98  H, H                                                                                       ##STR193##  1603, 1450, 1417, 1392, 1223, 1154, 775,                                      750, 720    CDCl3: 7.7-7.1m(7H),                                                          6.4-6.2m(2H), 3.1t(2H),                                                       2.8t(2H), 2.0tt(2H)                                                                          117.9-118.9           99  H, H                                                                                       ##STR194##  2950, 2929, 1526, 1453, 1220, 841, 749,                                                   CDCl3: 7.7-7.4m(3H), 7.3s(1H),                                                7.2-7.0 m(2H), 6.4-6.2m(2H),                                                  3.0t(2H), 2.8t(2H),                                                                          114.3-116.5          100  H, H                                                                                       ##STR195##  1512, 1450, 1004, 833, 748,                                                               CDCl3: 7.7d(1H), 7.5-7.4m(4H),                                                7.4s (1H), 6.5-6.2m(2H),                                                      3.0t(2H), 2.8t(2H),                                                                          131.0-133.8          101  H, H                                                                                       ##STR196##  2928, 1510, 1450, 1223, 1000, 832, 749,                                                   CDCl3: 7.8-7.6m(3H),                                                          7.4-7.1m(3H), 6.4-6.2m(2H),                                                   3.0t(2H), 2.8t (2H),                                                                         132.3-139.7          102  H, H                                                                                       ##STR197##  1594, 1517, 1506, 1449, 1328, 1317, 1108,                                     853, 759    CDCl3: 8.3d(2H), 7.7-7.6m(3H),                                                7.5s (1H), 6.5-6.2m(2H),                                                      3.1t(2H), 2.9t(2H),                                                                          145.5-147.1          103  H, H                                                                                       ##STR198##  2223, 1605, 1522, 1447, 1405, 1388, 1178,                                     843, 761, 754                                                                             CDCl3: 7.8d(1H), 7.7s(4H),                                                    7.4s(1H), 6.5-6.2m(2H),                                                       3.0t(2H), 2.9t (2H),                                                                         144.5-145.7          104  H, H                                                                                       ##STR199##  1709, 1605, 1435, 1283, 1274, 1224, 1180,                                     1102, 750   CDCl3: 8.1d(2H), 7.7-7.6m(3H),                                                7.5s (1H), 6.5-6.2m(2H),                                                      3.9s(3H), 3.1t(2H), 2.8t(2H),                                                 2.1tt(2H)      118.0-120.2          105  H, H                                                                                       ##STR200##  2930, 2916, 1509, 1450, 1440, 1216, 823,                                      805, 758    CDCl3: 7.7dd(1H), 7.5dd(1H),                                                  7.4s(1H), 7.4-7.2m(2H),                                                       6.5-6.2m(2H), 2.8t(4H),                                                       2.0tt(2H)      79.9-80.8            106  H, H                                                                                       ##STR201##  2923, 1535, 1527, 1445, 1238, 831,                                                        CDCl3: 7.7d(1H), 7.5d(2H),                                                    7.3s(1H), 6.9d(2H),                                                           6.4-6.2m(2H), 4.9brs (1H),                                                    3.0t(2H), 2.8t(2H), 2.0tt(2H)                                                                172.6-175.3          107  H, H                                                                                       ##STR202##  2914, 2831, 1528, 1452, 1248, 1181, 1035,                                     749         CDCl3: 7.7d(1H), 7.5d(2H),                                                    7.3s(1H), 6.9d(2H),                                                           6.4-6.1m(2H), 3.8s (3H),                                                      3.0t(2H), 2.8t(2H), 2.0tt(2H)                                                                103.9-105.2          108  H, H                                                                                       ##STR203##  1654, 1451, 823, 746, 728                                                                 CDCl3: 8.0-7.3m(9H),                                                          6.5-6.2m(2H), 3.2t(2H),                                                       2.9t(2H), 2.1tt(2H)                                                                          141.1-144.2          109  H, H                                                                                       ##STR204##  2921, 2837, 1536, 1450, 1404, 1390, 1302,                                     1224, 825, 747, 734                                                                       CDCl3: 7.6d(1H), 7.5d(2H),                                                    7.4s(1H), 7.2d(2H),                                                           6.4-6.2m(2H), 3.0t(2H),                                                       2.8t(2H), 2.4s(3H),                                                                          106.1-107.3          110  H, H                                                                                       ##STR205##  2922, 2832, 1589, 1446, 1419, 1382, 1099,                                     1024, 802, 755                                                                            CDCl3: 7.7d(1H), 7.5-7.1m(4H),                                                6.5- 6.2m(2H), 2.9t(4H),                                                      2.0tt(2H)      109.6-111.5          111  H, H                                                                                       ##STR206##  1446, 1436, 1433, 1418, 1214, 751, 739,                                                   CDCl3: 7.7d(1H), 7.5-7.1m(5H),                                                6.5- 6.2m(2H), 2.9t(4H),                                                      2.0tt(2H),     115.2-116.2          112  H, H                                                                                       ##STR207##  2938, 1598, 1565, 1561, 1452, 751,                                                        CDCl3: 7.7d(1H), 7.6-7.1m(5H),                                                6.5-6.2 m(2H), 3.0t(2H),                                                      2.8t(2H), 2.0tt (2H)                                                                         72.3-74.7            113  H, H                                                                                       ##STR208##  2929, 1446, 1430, 1418, 1213, 752, 739,                                                   CDCl3: 7.8-7.6m(2H),                                                          7.4-7.0m(4H), 6.5-6.2m(2H),                                                   2.8t(4H), 2.0tt (2H)                                                                         126.1-126.7          114  H, H                                                                                       ##STR209##  2931, 2829, 1593, 1558, 1554, 1451,1407,                                      750, 736, 715                                                                             CDCl3: 7.8-7.1m(6H),                                                          6.5-6.2m(2H), 3.0t(2H),                                                       2.8t(2H), 2.0tt(2H)                                                                          64.3-70.0            115  H, H                                                                                       ##STR210##  1596, 1588, 1554, 1543, 1533, 1387, 747,                                      733         DMSO-d6: 8.0-7.8m(3H),                                                        7.7s(1H), 7.4d (2H),                                                          6.5-6.2m(2H), 2.9t(2H),                                                       2.7t(2H), 1.9tt(2H)                                                                          >300                 116  H, OH                                                                                      ##STR211##  3345, 3303, 1517, 1452, 1092, 834,                                                        DMSO-d6: 8.0dd(1H), 7.8s(1H),                                                 7.6d(2H), 7.4d(2H),                                                           6.6-6.4m(2H), 4.8dd (1H),                                                     3.0t(2H), 2.3-1.7m(2H)                                                                       170.6-173.8          117  NNH.sub.2                                                                                  ##STR212##  1533, 1447, 1440, 1401, 1389, 1289, 1093,                                     835, 766, 738, 730                                                                        CDCl3: 7.8dd(1H), 7.6-7.3m(4H),                                               7.4s (1H), 6.9d(1H), 6.5dd(1H),                                               5.5 brs(2H), 3.2t(2H),                                                                       181.8-182.1          118  NOCH.sub.3                                                                                 ##STR213##  1515, 1448, 1401, 1051, 1010, 853, 830,                                                   CDCl3: 7.8dd(1H), 7.6-7.3m(4H),                                               7.4s (1H), 7.0d(1H), 6.5dd(1H),                                               4.0s (3H), 3.2-2.9m(4H)                                                                      139.5-141.3          119                                                                                 ##STR214##                                                                                ##STR215##  1601, 1577, 1571, 1528, 1501, 1474, 1251,                                     1143, 1091, 752                                                                           CDCl3: 7.8d(1H), 7.6brs(1H),                                                  7.5-7.0m (10H), 7.0-6.7m(1H),                                                 6.5dd (1H), 3.3t(2H),                                                                        156.6-158.4          120  NNH.sub.2                                                                                  ##STR216##  1685, 1654, 1648, 1590, 1578, 1381, 804,                                      778, 758    CDCl3: 8.0-7.6m(9H), 7.0d(1H),                                                6.5dd (1H), 5.5brs(2H),                                                       3.1-2.4m(4H)   110.7-116.3          121  NNH.sub.2                                                                                  ##STR217##  3401, 1629, 1625, 1600, 1447,                                                             CDCl3: 8.0-7.3m(9H), 7.0d(1H),                                                6.5dd (1H), 5.6brs(2H),                                                       3.4t(2H), 2.8t(2H)                                                                           175.7-179.3          122  H, NHCOCO.sub.2 C.sub.2 H.sub.5                                                            ##STR218##  3238, 1751, 1701, 1686, 1519, 1452, 1205,                                     736         CDCl3: 7.8dd(1H), 7.6-7.3m(6H),                                               6.5- 6.3m(2H), 5.5-5.1m(1H),                                                  4.4q (2H), 3.3-3.0m(2H),                                                      2.4-2.0m (2H),                                                                               175.4-176.8          123                                                                                 ##STR219##                                                                                ##STR220##  3151, 1401, 1390, 1340, 1333, 1316, 1157,                                     1091, 679   DMSO-d6: 10.8s(1H), 8.1d(1H),                                                 8.0-7.3m (9H), 6.8d(1H),                                                      6.5dd(1H), 3.3- 2.6m(4H),                                                     2.4s(3H)       205.0-205.9          124  NNC(CH.sub.3).sub.2                                                                        ##STR221##  2909, 2840, 1627, 1449, 1402, 833, 755,                                                   CDCl3: 7.8d(1H), 7.6-7.1m(6H),                                                6.5dd (1H), 3.3-2.9m(4H),                                                     2.1s(3H),  2.0s(3H)                                                                          103.8-106.1          125  NOCH.sub.3                                                                                 ##STR222##  2926, 1601, 1448, 1390, 1049, 854, 758,                                       731, 700    *DMSO-d6: 8.2d(1H), 7.8s(1H),                                                 7.6d(2H), 7.4dd(2H), 7.3t(1H),                                                6.8d(1H), 66dd(1H), 4.0s(3H),                                                 3.1t(2H), 3.0t(2H)                                                                           82.0-83.9            126  NNHCH.sub.3                                                                                ##STR223##  3259, 1581, 1531, 1444, 1146, 1095, 835,                                      762, 737, 681                                                                             *DMSO-d6: 8.0d(1H), 7.8s(1H),                                                 7.6d(2H), 7.5d(2H), 6.8d(1H),                                                 6.7brs(1H), 6.5dd(1H),                                                        3.1t(2H), 3.0s(3H), 2.7t(2H)                                                                 179.0-180.1          127  H, OCOCH.sub.3                                                                             ##STR224##  1734, 1518, 1454, 1369, 1238, 1090, 1026,                                     833, 739    *DMSO-d6: 8.1dd(1H), 7.8s(1H),                                                7.6d(2H), 7.5d(2H),                                                           6.6-6.5m(2H), 6.0dd (1H),                                                     3.1dd(2H), 2.3-2.0m(2H),                                                      2.1s(3H)       116.5-118.6          128  NOCH.sub.2 CO.sub.2 H                                                                      ##STR225##  2922, 1738, 1435, 1259, 1095, 993, 870,                                                   *DMSO-d6: 12.8s(1H), 8.2d(1H),                                                7.9s(1H), 7.6d(2H), 7.5d(2H),                                                 6.8d(1H), 6.6dd(1H), 4.7s(2H),                                                3.14t(2H), 3.05t(2H)                                                                         201.1-202.0          129                                                                                 ##STR226##                                                                                ##STR227##  1751, 1514, 1446, 1406, 1209, 1095, 1026,                                     847, 835    *DMSO-d6: 8.2d(1H), 7.9s(1H),                                                 7.6d(2H), 7.5d(2H), 6.8d(1H),                                                 6.6dd(1H), 4.8s(2H), 3.7s(3H),                                                3.15t(2H), 3.05t(2H)                                                                         139.4-140.1          130  H, H                                                                                       ##STR228##  2935, 1618, 1329, 1161, 1120, 1072, 849,                                      754         *DMSO-d6: 8.0d(1H), 7.84s(1H),                                                7.79d(2H), 7.7d(2H), 6.5dd(1H),                                               6.3d(1H), 3.0t(2H), 2.8t(2H),                                                 2.0- 1.9m(2H)  119.3-120.0          131  H, NH.sub.2                                                                                ##STR229##  3406, 3359, 1512, 1448, 1223, 835, 754,                                                   *DMSO-d6: 8.0d(1H), 7.8s(1H),                                                 7.6d(2H), 7.5d(2H), 6.6d(1H),                                                 6.5dd (1H), 4.0dd(1H),                                                        3.0-2.9m(2H), 2.2-2.0m(1H),                                                   1.8-1.7m(1H)   158.0-159.5          132  H, NH.sub.2                                                                                ##STR230##  3406, 1618, 1333, 1167, 1107, 1072, 851,                                      764, 741    *DMSO-d6: 8.0d(1H), 7.9s(1H),                                                 7.8d(2H), 7.7d(2H), 6.6d(1H),                                                 6.5dd (1H), 4.0d(1H),                                                         3.1-3.0m(2H), 2.2-2.1m(1H),                                                   1.9- 1.7m(1H)  149.1-152.4          133  H, NH.sub.2                                                                                ##STR231##  3367, 1527, 1450, 1248, 1178, 1030, 837,                                      737         DMSO-d6: 7.9d(1H), 7.6s(1H),                                                  7.5d(2H), 7.0d(2H),                                                           6.6-6.3m(2H), 4.0dd (1H),                                                     3.8s(3H), 3.3-2.7m(2H),                                                       2.3-1.5m(2H)   114.5-117.4          134  H, NH.sub.2                                                                                ##STR232##  3273, 1581, 1552, 1514, 1448, 1373, 1313,                                     739         *DMSO-d6: 8.0d(1H), 7.7s(1H),                                                 7.6s(1H), 7.5s(2H), 6.6d(1H),                                                 6.5dd(1H), 4.0dd(1H),                                                         2.9-2.6m(2H), 2.1- 2.0m(1H),                                                  1.8-1.7m(1H)   79.4-81.9            135  H, NH.sub.2                                                                                ##STR233##  3431, 1595, 1497, 1452, 1335, 1109, 852,                                      729         *DMSO-d6: 8.3d(2H), 8.01d(1H),                                                7.96s(1H), 7.9d(2H), 6.6d(1H),                                                6.5dd(1H), 4.0dd(1H),                                                         3.2-3.0m(2H), 2.2- 2.0m(1H),                                                  1.9-1.7m(1H)   149.1-152.5          136  H, NH.sub.2                                                                                ##STR234##  3402, 3367, 2931, 1601, 1450, 760, 739,                                                   *DMSO-d6: 8.0d(1H), 7.7s(1H),                                                 7.6d(2H), 7.4dd(2H), 7.2t(1H),                                                6.6d(1H), 6.5dd(1H), 4.0dd(1H),                                               3.1-2.9m (2H), 2.2-2.0m(1H),                                                  1.9- 1.7m(1H)  127.5-129.7          137  H, NH.sub.2                                                                                ##STR235##  3377, 2918, 1628, 1599, 1448, 858, 822,                                       756, 739    *DMSO-d6: 8.1s(1H), 8.0d(1H),                                                 8.0-7.9m (4H), 7.8d(1H),                                                      7.6-7.4m(2H), 6.6d(1H),                                                       6.5dd(1H), 4.1d(1H), 3.3-3.0m(2H                                              ), 2.3-2.1m(1H), 2.0-1.8m(1H)                                                                141.8-143.7          138  NOCH.sub.3                                                                                 ##STR236##  1616, 1323, 1230, 1174, 1163, 1124, 1070,                                     1057, 841   *DMSO-d6: 8.2d(1H), 8.0s(1H),                                                 7.81d(2H), 7.77d(2H), 6.9d(1H),                                               6.6dd(1H), 4.0s(3H), 3.2t(2H),                                                3.0t(2H)       117.9-119.5          139  H, NH.sub.2                                                                                ##STR237##  3352, 2916, 1537, 1450, 1379, 825, 762,                                                   *DMSO-d6: 8.0d(1H), 7.7s(1H),                                                 7.5d(2H), 7.2d(2H), 6.54d(1H),                                                6.46dd (1H), 4.0dd(1H),                                                       3.1-2.9m(2H), 2.3s(3H),                                                       2.2-2.0m(1H),                                                                                120.5-121.8H)        140  NOCH.sub.3                                                                                 ##STR238##  1595, 1504, 1342, 1115, 1043, 860, 849,                                                   DMSO-d6: 8.3d(2H), 8.2d(1H),                                                  8.0s(1H), 7.8d(2H), 6.9d(1H),                                                 6.6dd(1H), 4.0s(3H),                                                          3.3-2.9m(4H)   158.4-159.0          141  H, NH.sub.2                                                                                ##STR239##  3367, 2912, 1578, 1525, 1269, 1209,                                                       *DMSO-d6: 8.1d(1H), 7.83s(1H),                                                7.77d(2H), 7.5d(2H), 6.7d(1H),                                                6.6dd(1H), 4.1-4.0m(1H),                                                      3.2-3.0m(2H), 2.2-2.1m(1H),                                                   2.0-1.8m(1H)   102.9-106.0          142                                                                                 ##STR240##                                                                                ##STR241##  3198, 1724, 1702, 1542, 1533, 1260, 1245,                                     1092        DMSO-d6: 10.4s(1H), 8.1d(1H),                                                 7.8s(1H), 7.6d(2H), 7.5d(2H),                                                 6.9d(1H), 6.6t(1H), 4.2q(2H),                                                 3.3-2.7m (4H),                                                                               204.9-206.0          143                                                                                 ##STR242##                                                                                ##STR243##  3275, 1649, 1541, 1532, 1517, 1451, 1092,                                     738         CDCl3: 7.7-7.3m(6H),                                                          6.5-6.4m(2H), 6.0-5.8m(1H),                                                   5.5-5.3m(1H), 3.1-3.0m(2H),                                                   2.9t(2H), 2.5t (2H), 2.2s(3H),                                                2.2-2.0m(2H)   200.2-201.7          144                                                                                 ##STR244##                                                                                ##STR245##  1595, 1574, 1498, 1443, 1138,                                                             CDCl3: 8.4brs(1H), 8.1d(1H),                                                  7.8d(1H), 7.7-7.1m(8H),                                                       6.9-6.7m(1H), 6.5t(1H),                                                       3.3t(2H), 2.9t(2H)                                                                           161.2-162.7          145                                                                                 ##STR246##                                                                                ##STR247##  3136, 1655, 1610, 1402, 1290, 1068,                                                       DMSO-d6: 11.6brs(1H),                                                         8.4brs(1H), 8.2d (1H),                                                        7.9s(1H), 7.6d(2H), 7.5d (2H),                                                7.3d(1H), 6.6t(1H), 3.8s (4H),                                                3.3-3.1m(2H), 3.1-2.8m(2H)                                                                   236.4-(dec.)         146                                                                                 ##STR248##                                                                                ##STR249##  3392, 3271, 3161, 1673, 1624, 1600, 1126,                                     1093, 760   DMSO-d6: 11.7brs(1H), 8.2d(1H),                                               8.0 brs(3H), 7.9s(1H),                                                        7.6d(2H), 7.5d(2H), 7.4d(1H),                                                 6.6t(1H), 3.3-2.9m(4H)                                                                       229.8-(dec.)         147                                                                                 ##STR250##                                                                                ##STR251##  1404, 1095, 1067, 1040, 1001, 846, 837,                                                   DMSO-d6: 8.2d(1H), 7.8s(1H),                                                  7.6d(2H), 7.4d(2H), 6.9d(1H),                                                 6.5t(1H), 5.6s(2H),                                                           3.2-2.9m(4H)   193.7-(dec.)         148  H, OH                                                                                      ##STR252##  3338, 1618, 1329, 1161, 1119, 1072, 845,                                      741         *DMSO-d6: 8.1-8.0m(1H),                                                       7.9s(1H), 7.81d (2H),                                                         7.75d(2H), 6.6-6.5m(2H),                                                      5.4d(1H), 4.9-4.7m(1H), 3.1-                                                  3.0m(2H), 2.2-1.8m(2H)                                                                       147.2-148.0          __________________________________________________________________________

The following examples detail typical pharmaceutical preparationscontaining the compound of the present invention, but are not intendedto limit this invention.

EXAMPLE A CAPSULES

    ______________________________________                                        compound of Example 3                                                                             50 g                                                      lactose            935 g                                                      magnesium stearate  15 g                                                      ______________________________________                                    

Above ingredients were weighed and mixed until the mixture becomehomogeneous. The mixture was then filled in No. 1 hard capsule at 200 mgeach to obtain capsule preparation.

EXAMPLE B CAPSULES

50 g of compounds of Example 71 was formulated into capsules in the samemanner of example A.

EXAMPLE C TABLETS

    ______________________________________                                        compound of Example 12                                                                             50 g                                                     lactose             755 g                                                     potato starch       165 g                                                     polyvinyl alcohol    15 g                                                     magnesium stearate   15 g                                                     ______________________________________                                    

After each ingredient was weighed, the compound, lactose and potatostarch were mixed to be homogeneous. To this mixture was added polyvinylalcohol aq. and made into granule by wet granulation. After drying, thegranule was mixed with magnesium stearate and formulated into tabletsweighing 200 mg each by compression.

EXAMPLE D TABLETS

50 g of compounds of Example 130 was formulated into tablets eachweighing 200 mg in the same manner of Example C

INDUSTRIAL UTILITY FIELD

The compound of the present invention is capable of sufficientlyinhibiting the production of IgE antibody for a prolonged period, and atthe same time, it gives no significant influence on the production ofimmunoglobulins other than the IgE antibody. In addition, the compoundof the present invention has low toxicity. Accordingly, the compound ofthe present invention may be advantageously used in the prevention ofallergic diseases, prevention of the manifestation of the allergicsymptoms, prevention of exacerbation of the symptoms, and ameliorationand cure of the symptoms. The allergic diseases mediated by IgE antibodythat may be treated or prevented by the compound of the presentinvention include bronchial asthma, conjunctivitis, rhinitis, dermatis,hypersensitivity, and other allergic diseases.

We claim:
 1. A nitrogen-containing tricyclic compound represented byformula (I): ##STR253## a salt thereof, or a solvate of said compound orsaid salt, wherein R represents phenyl or naphthyl group which isunsubstituted or substituted at one to five sites with a groupoptionally selected from a halogen atom; a straight chain or branchedalkyl group containing 1 to 10 carbon atoms which is unsubstituted orsubstituted with one or more halogen atoms; cyano group; carboxyl group;an alkoxycarbonyl group containing 1 to 4 carbon atoms; hydroxyl group;a straight chain or branched alkoxyl group containing 1 to 4 carbonatoms which is unsubstituted or substituted with one or more halogenatoms; phenoxy group; tetrazolyl group; amino group which isunsubstituted or substituted at least at one site with a straight chainor branched atkyl group containing 1 to 4 carbon atoms; and nitrogroup;Y represents hydrogen atom; and Z represents hydrogen atom;hydroxyl group; acetoxy group; an amino group which is unsubstituted orsubstituted with methylthiopropanoyl group, an alkyl group containing 1to 4 carbon atoms, an aminoalkyl group containing 1 to 4 carbon atoms, ahydroxyethylaminoethyl group, an alkoxyoxalyl group containing 1 to 4carbon atoms, or an alkylidene group containing 2 to 6 carbon atoms;nitro group; or an alkyl group containing 1 to 4 carbon atomssubstituted with amino group; or Y and Z together represent hydrazonogroup which is unsubstituted or substituted at least at one site with analkyl group containing 1 to 4 carbon atoms, an alkylidene groupcontaining 2 to 6 carbon atoms, an alkoxycarbonyl group containing 1 to4 carbon atoms, phenyl group, tosyl group, formyl group, carbamoylgroup, amidino group, imidazolidinyl group, pyridyl group, ormethoxyphenylethylpiperidinylcarbonyl group; hydroxyimino group which isunsubstituted or substituted with an alkyl group containing 1 to 4carbon atoms which is unsubstituted or substituted with analkoxycarbonyl group containing 1 to 4 carbon atoms or carboxyl group,tosyl group, or tetrazolylmethyl group; imino group substituted with anunsubstituted or substituted heteromonocyclic group; methylene groupwhich is unsubstituted or substituted with cyano group or an aminoalkylgroup containing 1 to 4 carbon atoms; or oxygen atom; and X¹ -X² ˜C˜X³represents CH--N--C═C; excluding the following both compounds wherein Yand Z together represent oxygen and R represents unsubstituted phenylgroup; and Y and Z represent hydrogen, R represents unsubstituted phenylgroup, 4-methoxy phenyl group, 4-bromo phenyl group, and 2-naphthylgroup.
 2. A compound, a salt thereof, or a solvate of said compound orsaid salt according to claim 1, whereinsaid R is phenyl or naphthylgroup which is unsubstituted or substituted at one to five sites with agroup optionally selected from a halogen atom; a straight chain orbranched alkyl group containing 1 to 10 carbon atoms which isunsubstituted or substituted with one or more halogen atoms; a straightchain or branched alkoxyl group containing 1 to 4 carbon atoms which isunsubstituted or substituted with one or more halogen atoms; phenoxygroup; and nitro group.
 3. A compound, a salt thereof, or a solvate ofsaid compound or said salt according to claim 2, whereinsaid Yrepresents hydrogen atom; and Z represents hydrogen atom, hydroxylgroup, acetoxy group, or amino group; or Y and Z together representhydroxyimino group which is unsubstituted or substituted with an alkylgroup containing 1 to 4 carbon atoms; methylene group which isunsubstituted or substituted with cyano group or an aminoalkyl groupcontaining 1 to 4 carbon atoms; or oxygen atom.
 4. A compound, a saltthereof, or a solvate of said compound or said salt according to claim3, whereinsaid R is phenyl group substituted at one or two sites with agroup optionally selected from a halogen atom; a straight chain orbranched alkyl group containing 1 to 4 carbon atoms which is substitutedwith one or more halogen atoms; and a straight chain or branched alkoxylgroup containing 1 to 4 carbon atoms which is substituted with one ormore halogen atoms.
 5. A prophylactic and/or therapeutic composition forallergic disease comprising an effective amount to treat said allergicdisease of a compound represented by formula (I) of claim 1, a saltthereof, or a solvate of said compound or said salt, and apharmaceutically acceptable carrier.
 6. A method for preventing and/ortreating an allergic disease, comprising administering to a patient inneed of said treatment an effective amount of a compound represented byformula (I) of claim 1, a salt thereof, or a solvate of said compound orsaid salt.
 7. The nitrogen-containing tricyclic compound according toclaim 1, wherein R is a phenyl group or naphthyl group that issubstituted with a halogen atom; Y is a hydrogen atom; and Z is an aminogroup.
 8. A nitrogen-containing tricyclic compound represented by7-amino-1- (4-chlorophenyl)-8,9-dihydro-7H-pyrrolo (3,2,1-ij)quinoline.9. A process for producing a compound represented by formula (I) ofclaim 1, a salt thereof, or a solvate of said compound or said salt,characterized in that said process comprisesa) reacting a ketonederivative represented by formula (II): ##STR254## wherein R representsphenyl or naphthyl group which is unsubstituted or substituted at one tofive sites with a group optionally selected from a halogen atom; astraight chain or branched alkyl group containing 1 to 10 carbon atomswhich is unsubstituted or substituted with one or more halogen atoms;cyano group; carboxyl group; an alkoxycarbonyl group containing 1 to 4carbon atoms; hydroxyl group; a straight chain or branched alkoxyl groupcontaining 1 to 4 carbon atoms which is unsubstituted or substitutedwith one or more halogen atoms; phenoxy group; tetrazolyl group; aminogroup which is unsubstituted or substituted at least at one site with astraight chain or branched alkyl group containing 1 to 4 carbon atoms;and nitro group; and X¹ -X² ˜C˜X³ represents CH--N--C═C; with hydrazineor a salt thereof to produce a hydrazone derivative correspondingthereto; reacting hydrazono group of said hydrazone derivative withacetone or a compound represented by formula (III):

    R.sup.1 -X                                                 (III),

wherein X is a leaving group and R¹ is phenyl group or tosyl group; andsubjecting the resulting product to an optional reducing treatment; b)reacting said compound of formula (II) with a compound represented byformula (IV):

    H.sub.2 N-R.sup.2                                          (IV),

or a salt thereof, wherein R² is amino group which is unsubstituted orsubstituted with an alkyl group containing 1 to 4 carbon atoms, analkylidene group containing 2 to 6 carbon atoms, an alkoxylcarbonylgroup containing 1 to 4 carbon atoms, phenyl group, tosyl group, formylgroup, carbamoyl group, amidino group, imidazolidinyl group, pyridylgroup, or methoxyphenylethylpiperidinylcarbonyl group; hydroxyl groupwhich is unsubstituted or substituted with an alkyl group containing 1to 4 carbon atoms which is unsubstituted or substituted with analkoxycarbonyl group containing 1 to 4 carbon atoms or carboxyl group,tosyl group, or tetrazolylmethyl group; or an unsubstituted orsubstituted heteromonocyclic group; and subjecting the resulting productto an optional reducing treatment; or c) treating said compound offormula (II) with a reducing agent to produce a hydroxy derivative;optionally halogenating said hydroxy derivative with a halogenatingagent; and aminating the compound to product an amino derivative;reacting said compound of formula (II) with ammonium acetate; andsubjecting the resulting product to a reducing treatment followed by anoptional hydrolysis to produce an amino derivative; reacting saidcompound of formula (II) with hydroxylamine or its salt to produce anoxime derivative; then reducing said oxime derivative to produce anamino derivative; and optionally reacting said amino derivative with analkoxyoxalyl halide containing 1 to 4 carbon atoms; reacting said oximederivative with an alkyl halide containing 1 to 4 carbon atoms or tosylhalide which is unsubstituted or substituted with carboxyl group tomodify the oxime group; reacting said compound of formula (II) with acompound represented by formula (IV')

    H.sub.2 N-R.sup.2'                                         (IV')

wherein R² is an alkyl group containing 1 to 4 carbon atoms, anaminoalkyl group containing 1 to 4 carbon atoms, orhydroxyethylaminoethyl group; and reducing the resulting compound toproduce an amino derivative; reacting said compound of formula (II) withan alkylphosphonium salt containing 1 to 4 carbon atoms which isunsubstituted or substituted with cyano group or amino group or an alkylphosphate ester corresponding thereto in the presence of a base such aspotassium hydroxide, potassium t-butoxide, or butyllithium; or reducingketone group of said compound of formula (II) to hydroxyl group;followed halogenating or sulfonylating the hydroxyl group to produce ahalogenated derivative or sulfonyloxy derivative; and reducing saidhalogenated derivative or said sulfonyloxy derivative.
 10. A process forproducing a 8,9-dihydro-7H-pyrrolo-[3,2,1-ij]quinoline derivativerepresented by formula (VIII): ##STR255## a salt thereof, or a solvateof said derivative or said salt, wherein R represents phenyl or naphthylgroup which is unsubstituted or substituted at one to five sites with agroup optionally selected from a halogen atom; a straight chain orbranched alkyl group containing 1 to 10 carbon atoms which isunsubstituted or substituted with one or more halogen atoms; cyanogroup; carboxyl group; an alkoxycarbonyl group containing 1 to 4 carbonatoms; hydroxyl group; a straight chain or branched alkoxyl groupcontaining 1 to 4 carbon atoms which is unsubstituted or substitutedwith one or more halogen atoms; phenoxy group; tetrazolyl group; aminogroup which is unsubstituted or substituted at least at one site with astraight chain or branched alkyl group containing 1 to 4 carbon atoms;and nitro group; andY represents hydrogen atom; and Z representshydrogen atom; hydroxyl group; acetoxy group; amino group which isunsubstituted or substituted with methylthiopropanoyl group, an alkylgroup containing 1 to 4 carbon atoms, an aminoalkyl group containing 1to 4 carbon atoms, hydroxyethylaminoethyl group, an alkoxyoxalyl groupcontaining 1 to 4 carbon atoms, or an alkylidene group containing 2 to 6carbon atoms; nitro group; or an alkyl group containing 1 to 4 carbonatoms substituted with amino group; or Y and Z together representhydrazono group which is unsubstituted or substituted at least at onesite with an alkyl group containing 1 to 4 carbon atoms, an alkylidenegroup containing 2 to 6 carbon atoms, an alkoxycarbonyl group containing1 to 4 carbon atoms, phenyl group, tosyl group, formyl group, carbamoylgroup, amidino group, imidazolidinyl group, pyridyl group, ormethoxyphenylethylpiperidinylcarbonyl group; hydroxyimino group which isunsubstituted or substituted with an alkyl group containing 1 to 4carbon atoms which is unsubstituted or substituted with analkoxycarbonyl group containing 1 to 4 carbon atoms or carboxyl group,tosyl group, or tetrazolylmethyl group; imino group substituted with anunsubstituted or substituted heteromonocyclic group; methylene groupwhich is unsubstituted or substituted with cyano group or an aminoalkylgroup containing 1 to 4 carbon atoms; or oxygen atom; excluding thefollowing compounds wherein: Y and Z together represent oxygen and Rrepresents unsubstituted phenyl group and Y and Z represent hydrogen, Rrepresents unsubstituted phenyl group, 4-methoxy phenyl group, 4-bromophenyl group, and 2-phenyl group;characterized in that said processcomprises reacting a 5,6,7,8-tetrahydroquinoline derivative representedby formula (V): ##STR256## wherein Y represents hydrogen atom; and Zrepresents hydrogen atom; hydroxyl group; acetoxy group; amino groupwhich is unsubstituted or substituted with methylthiopropanoyl group, analkyl group containing 1 to 4 carbon atoms, an aminoalkyl groupcontaining 1 to 4 carbon atoms, hydroxyethylaminoethyl group, analkoxyoxalyl group containing 1 to 4 carbon atoms, or an alkylidenegroup containing 2 to 6 carbon atoms; nitro group; or an alkyl groupcontaining 1 to 4 carbon atoms substituted with amino group; or Y and Ztogether represent hydrazono group which is unsubstituted or substitutedat least at one site with an alkyl group containing 1 to 4 carbon atoms,an alkylidene group containing 2 to 6 carbon atoms, an alkoxycarbonylgroup containing 1 to 4 carbon atoms, phenyl group, tosyl group, formylgroup, carbamoyl group, amidino group, imidazolidinyl group, pyridylgroup, or methoxyphenylethylpiperidinylcarbonyl group; hydroxyiminogroup which is unsubstituted or substituted with an alkyl groupcontaining 1 to 4 carbon atoms which is unsubstituted or substitutedwith an alkoxycarbonyl group containing 1 to 4 carbon atoms or carboxylgroup, tosyl group, or tetrazolylmethyl group; imino group substitutedwith an unsubstituted or substituted heteromonocyclic group; methylenegroup which is unsubstituted or substituted with cyano group oraminoalkyl group containing 1 to 4 carbon atoms; or oxygen atom;with anaromatic ketone derivative represented by formula (IV):

    X--CH.sub.2 CO--R                                          (IV)

wherein X is a leaving group, and R represents phenyl or naphthyl groupwhich is unsubstituted or substituted at one to five sites with a groupselected from a halogen atom; a straight chain or branched alkyl groupcontaining 1 to 10 carbon atoms which is unsubstituted or substitutedwith one or more halogen atoms; cyano group; carboxyl group; analkoxycarbonyl group containing 1 to 4 carbon atoms; hydroxyl group; astraight chain or branched alkoxyl group containing 1 to 4 carbon atomswhich is unsubstituted or substituted with one or more halogen atoms;phenoxy group; tetrazolyl group; amino group which is unsubstituted orsubstituted at least at one site with a straight chain or branched alkylgroup containing 1 to 4 carbon atoms; and nitro group; to produce a5,6,7,8-tetrahydroquinolinium salt represented by formula (VII):##STR257## wherein X represents a leaving group; R represents phenyl ornaphthyl group which is unsubstituted or substituted at one to fivesites with a group optionally selected from a halogen atom; a straightchain or branched alkyl group containing 1 to 10 carbon atoms which isunsubstituted or substituted with one or more halogen atoms; cyanogroup; carboxyl group; an alkoxycarbonyl group containing 1 to 4 carbonatoms; hydroxyl group; a straight chain or branched chain alkoxyl groupcontaining 1 to 4 carbon atoms which is unsubstituted or substitutedwith one or more halogen atoms; phenoxy group; tetrazolyl group; aminogroup which is unsubstituted or substituted at least at one site with astraight chain or branched alkyl group containing 1 to 4 carbon atoms;and nitro group; Y represents hydrogen atom; and Z represents hydrogenatom; hydroxyl group; acetoxy group; amino group which is unsubstitutedor substituted with methylthiopropanoyl group, an alkyl group containing1 to 4 carbon atoms, an aminoalkyl group containing 1 to 4 carbon atoms,hydroxyethylaminoethyl group; an alkoxyoxalyl group containing 1 to 4carbon atoms, or an alkylidene group containing 2 to 6 carbon atoms;nitro group; or an alkyl group containing 1 to 4 carbon atomssubstituted with amino group; or Y and Z together represent hydrazonogroup which is unsubstituted or substituted at least at one site with analkyl group containing 1 to 4 carbon atoms, an alkylidene groupcontaining 2 to 6 carbon atoms, an alkoxycarbonyl group containing 1 to4 carbon atoms, phenyl group, tosyl group, formyl group, carbamoylgroup, amidino group, imidazolidinyl group, pyridyl group, ormethoxyphenylethylpiperidinylcarbonyl group; hydroxyimino group which isunsubstituted or substituted with an alkyl group containing 1 to 4carbon atoms which is unsubstituted or substituted with analkoxycarbonyl group containing 1 to 4 carbon atoms or carboxyl group,tosyl group, or tetrazolylmethyl group; imino group substituted with anunsubstituted or substituted heteromonocyclic group; methylene groupwhich is unsubstituted or substituted with cyano group or an aminoalkylgroup containing 1 to 4 carbon atoms; or oxygen atom; and reacting said5,6,7,8-tetrahydroquinolinium salt with a base.
 11. A process forproducing an 8,9-dihydro-7H-pyrrolo-[3,2,1-ij]quinoline derivativerepresented by formula (VIII): ##STR258## wherein R, Y and Z are asdefined for the formula (VIII) in claim 10, characterized in that saidprocess comprisesreacting a 5,6,7,8-tetrahydroquinoline derivativerepresented by formula (V): ##STR259## wherein Y and Z are as definedfor the formula (VIII) in claim 10 with an acetic acid derivativerepresented by formula (IX):

    X--CH.sub.2 COOR'                                          (IX)

wherein X is a leaving group, and R' represents a protective group forcarboxyl group to produce a 5,6,7,8-tetrahydroquinolinium derivativesalt represented by formula (X): ##STR260## wherein X represents a groupto be eliminated; Y represents hydrogen atom; and Z represents hydrogenatom; hydroxyl group; acetoxy group; amino group which is unsubstitutedor substituted with methylthiopropanoyl group, an alkyl group containing1 to 4 carbon atoms, an aminoalkyl group containing 1 to 4 carbon atoms,hydroxyethylaminoethyl group, an alkoxyoxalyl group containing 1 to 4carbon atoms, or an alkylidene group containing 2 to 6 carbon atoms;nitro group; or an alkyl group containing 1 to 4 carbon atomssubstituted with amino group; or Y and Z together represent hydrazonogroup which is unsubstituted or substituted at least at one site with analkyl group containing 1 to 4 carbon atoms, an alkylidene groupcontaining 2 to 6 carbon atoms, an alkoxycarbonyl group containing 1 to4 carbon atoms, phenyl group, tosyl group, formyl group, carbamoylgroup, amidino group, imidazolidinyl group, pyridyl group, ormethoxyphenylethylpiperidinylcarbonyl group; hydroxyimino group which isunsubstituted or substituted with an alkyl group containing 1 to 4carbon atoms which is unsubstituted or substituted with analkoxycarbonyl group containing 1 to 4 carbon atoms or carboxyl group,tosyl group, or tetrazolylmethyl group; imino group substituted with anunsubstituted or substituted heteromonocyclic group; methylene groupwhich is unsubstituted or substituted with cyano group or an aminoalkylgroup containing 1 to 4 carbon atoms; or oxygen atom; and R' representsa protective group for carboxyl group; reacting said5,6,7,8-tetrahydroquinolinium derivative salt with an acid anhydriderepresented by formula (XI):

    (RCO).sub.2 O                                              (XI)

wherein R is as defined for the formula (VIII) in claim 10; andhydrolyzing the resulting product.